Publications by authors named "Martin M Tisdall"

25 Publications

  • Page 1 of 1

Neurosurgical applications of tractography in the UK.

Br J Neurosurg 2020 Dec 14:1-6. Epub 2020 Dec 14.

Developmental Imaging and Biophysics Section, UCL GOS Institute of Child Health, London, UK.

Introduction: Tractography derived from diffusion MRI can provide important insights into human brain microstructure . Neurosurgeons were quick to adopt the technique at the turn of the century, but it remains plagued by technical fallibilities. This study aims to describe how tractography is deployed clinically in a modern-day, public healthcare system, serving as a snapshot from the 'shop floor' of British neurosurgical practice.

Methods: An 11-question survey was circulated to the mailing lists of the Society of British Neurological Surgeons and British Neurosurgical Trainees' Association, including questions on frequency, indication, tracts reconstructed, specific details of techniques used and personnel by whom it was performed, and a free-text section on the limitations of tractography.

Results: 58 survey responses were received, covering all 40 neurosurgical units in the UK and Ireland. Overall, responses were received from neurosurgeons at 36 units (90.0%) stating tractography was in use at that unit. 74.1% of the responses were from Consultants. The most common indication for tractography was in tumour resection. It was most commonly performed by neuroradiologists or imaging scientists. 75.9% of respondents stated that the model used to process tractography was the diffusion tensor (DTI). Many respondents were unaware of which algorithm (74.1%) or software tools (65.6%) were used by the operator to produce tractography visualisations. The corticospinal tract was the most commonly reconstructed tract. The most commonly cited limitations of the technique were perceived inaccuracy and brain shift.

Conclusions: In this UK-based survey of practising neurosurgeons, we show that 90% of neurosurgical units in the UK and Ireland use tractography regularly; that predominantly DTI-based reconstructions are used; that tumour resection remains the most frequent use of the technique; and that large tracts such as the corticospinal tract are most frequently identified. Many neurosurgeons remain unfamiliar with the underlying methods used to produce tractography visualisations.
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http://dx.doi.org/10.1080/02688697.2020.1849542DOI Listing
December 2020

Brain-Machine Interfaces: The Role of the Neurosurgeon.

World Neurosurg 2021 Feb 13;146:140-147. Epub 2020 Nov 13.

Developmental Neurosciences, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom; Department of Neurosurgery, Great Ormond Street Hospital, London, United Kingdom.

Neurotechnology is set to expand rapidly in the coming years as technological innovations in hardware and software are translated to the clinical setting. Given our unique access to patients with neurologic disorders, expertise with which to guide appropriate treatments, and technical skills to implant brain-machine interfaces (BMIs), neurosurgeons have a key role to play in the progress of this field. We outline the current state and key challenges in this rapidly advancing field, including implant technology, implant recipients, implantation methodology, implant function, and ethical, regulatory, and economic considerations. Our key message is to encourage the neurosurgical community to proactively engage in collaborating with other health care professionals, engineers, scientists, ethicists, and regulators in tackling these issues. By doing so, we will equip ourselves with the skills and expertise to drive the field forward and avoid being mere technicians in an industry driven by those around us.
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http://dx.doi.org/10.1016/j.wneu.2020.11.028DOI Listing
February 2021

Microelectrode recordings in human epilepsy: a case for clinical translation.

Brain Commun 2020 13;2(2):fcaa082. Epub 2020 Jun 13.

Developmental Neurosciences, Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.

With their 'all-or-none' action potential responses, single neurons (or units) are accepted as the basic computational unit of the brain. There is extensive animal literature to support the mechanistic importance of studying neuronal firing as a way to understand neuronal microcircuits and brain function. Although most studies have emphasized physiology, there is increasing recognition that studying single units provides novel insight into system-level mechanisms of disease. Microelectrode recordings are becoming more common in humans, paralleling the increasing use of intracranial electroencephalography recordings in the context of presurgical evaluation in focal epilepsy. In addition to single-unit data, microelectrode recordings also record local field potentials and high-frequency oscillations, some of which may be different to that recorded by clinical macroelectrodes. However, microelectrodes are being used almost exclusively in research contexts and there are currently no indications for incorporating microelectrode recordings into routine clinical care. In this review, we summarize the lessons learnt from 65 years of microelectrode recordings in human epilepsy patients. We cover the electrode constructs that can be utilized, principles of how to record and process microelectrode data and insights into ictal dynamics, interictal dynamics and cognition. We end with a critique on the possibilities of incorporating single-unit recordings into clinical care, with a focus on potential clinical indications, each with their specific evidence base and challenges.
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http://dx.doi.org/10.1093/braincomms/fcaa082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472902PMC
June 2020

Letter to the Editor. Systematic and safe approaches to innovation in pediatric pinning.

J Neurosurg Pediatr 2020 Aug 14:1-2. Epub 2020 Aug 14.

3National Hospital for Neurology and Neurosurgery, London, United Kingdom; and.

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http://dx.doi.org/10.3171/2020.5.PEDS20375DOI Listing
August 2020

The impact of social distancing on pediatric neurosurgical emergency referrals during the COVID-19 pandemic: a prospective observational cohort study.

Childs Nerv Syst 2020 09 3;36(9):1821-1823. Epub 2020 Jul 3.

Department of Neurosurgery, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1007/s00381-020-04783-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333974PMC
September 2020

Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: Country-, center-, and age-specific variation.

Epilepsia 2020 02 26;61(2):216-227. Epub 2019 Dec 26.

Neuroscience Department, Children's Hospital Meyer-University of Florence, Florence, Italy.

Objective: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015.

Methods: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries.

Results: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend = .0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend = .0047) and a significant decrease in unilobar temporal surgeries (P for trend = .0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015.

Significance: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures.
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http://dx.doi.org/10.1111/epi.16414DOI Listing
February 2020

SEEG-guided radiofrequency thermocoagulation of epileptic foci in the paediatric population: Feasibility, safety and efficacy.

Seizure 2019 Aug 3;70:63-70. Epub 2019 Jul 3.

Pediatric Neurosurgery, Rothschild Foundation, Paris, France.

Purpose: Focal epilepsy in children may be refractory to pharmacological treatment and surgical resection may be an appropriate option. When invasive electroencephalogram is required in the presurgical evaluation, depth electrodes can be used to create focal lesions in the epileptogenic zone using radiofrequency thermocoagulation (RFTC), to disrupt the epileptogenic zone.

Methods: This study aimed to assess the efficacy and safety of RFTC in a paediatric population of 46 patients.

Results: The mean age of onset was 3.3 years and the mean age at SEEG was 8.2 years. MRI lesions were identified in 71.7% of the series, among them 60% of malformation of cortical development. 43.5% of the patients were seizure free at 1 month, 26.1% were responders. The mean duration of improvement was 6.8 months. 8 children were seizure free for >8 months and among them, 6 are currently seizure free for 8-24 months. 5 patients had functional deficits post-procedures, transient in 4 patients and prolonged in one of whom. 3/5 were anticipated following the results of cortical stimulation. Multivariate analysis found 3 independent criteria linked to RFTC efficiency one month after RFTC: frequency of the seizures before RFTC, age and number of contacts used.

Conclusion: RFTC is a safe method for the paediatric population providing important predictive information for surgical resection. An improvement in seizure frequency, often transient, is seen in 2/3 of our patients. RTFC could be useful as a palliative technique for children with an epileptogenic zone overlapping with eloquent areas, with minimal risk of sequelae.
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http://dx.doi.org/10.1016/j.seizure.2019.07.004DOI Listing
August 2019

Accuracy of robot-assisted versus optical frameless navigated stereoelectroencephalography electrode placement in children.

J Neurosurg Pediatr 2019 01;23(3):297-302

2Institute of Child Health, London; and.

OBJECTIVE The aim of this study was to compare the accuracy of optical frameless neuronavigation (ON) and robot-assisted (RA) stereoelectroencephalography (SEEG) electrode placement in children, and to identify factors that might increase the risk of misplacement. METHODS The authors undertook a retrospective review of all children who underwent SEEG at their institution. Twenty children were identified who underwent stereotactic placement of a total of 218 electrodes. Six procedures were performed using ON and 14 were placed using a robotic assistant. Placement error was calculated at cortical entry and at the target by calculating the Euclidean distance between the electrode and the planned cortical entry and target points. The Mann-Whitney U-test was used to compare the results for ON and RA placement accuracy. For each electrode placed using robotic assistance, extracranial soft-tissue thickness, bone thickness, and intracranial length were measured. Entry angle of electrode to bone was calculated using stereotactic coordinates. A stepwise linear regression model was used to test for variables that significantly influenced placement error. RESULTS Between 8 and 17 electrodes (median 10 electrodes) were placed per patient. Median target point localization error was 4.5 mm (interquartile range [IQR] 2.8–6.1 mm) for ON and 1.07 mm (IQR 0.71–1.59) for RA placement. Median entry point localization error was 5.5 mm (IQR 4.0–6.4) for ON and 0.71 mm (IQR 0.47–1.03) for RA placement. The difference in accuracy between Stealth-guided (ON) and RA placement was highly significant for both cortical entry point and target (p < 0.0001 for both). Increased soft-tissue thickness and intracranial length reduced accuracy at the target. Increased soft-tissue thickness, bone thickness, and younger age reduced accuracy at entry. There were no complications. CONCLUSIONS RA stereotactic electrode placement is highly accurate and is significantly more accurate than ON. Larger safety margins away from vascular structures should be used when placing deep electrodes in young children and for trajectories that pass through thicker soft tissues such as the temporal region. ABBREVIATIONS CTA = CT angiography; IQR = interquartile range; MEG = magnetoencephalography; ON = optical frameless neuronavigation; RA = robot-assisted; SEEG = stereoelectroencephalography.
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http://dx.doi.org/10.3171/2018.10.PEDS18227DOI Listing
January 2019

Seizure and cognitive outcomes after resection of glioneuronal tumors in children.

Epilepsia 2018 01 26;59(1):170-178. Epub 2017 Nov 26.

Great Ormond Street Hospital, London, United Kingdom.

Objective: Glioneuronal tumors (GNTs) are well-recognized causes of chronic drug-resistant focal epilepsy in children. Our practice involves an initial period of radiological surveillance and antiepileptic medications, with surgery being reserved for those with radiological progression or refractory seizures. We planned to analyze the group of patients with low-grade GNTs, aiming to identify factors affecting seizure and cognitive outcomes.

Methods: We retrospectively reviewed the medical records of 150 children presenting to Great Ormond Street Hospital with seizures secondary to GNTs. Analysis of clinical, neuroimaging, neuropsychological, and surgical factors was performed to determine predictors of outcome. Seizure outcome at final follow-up was classified as either seizure-free (group A) or not seizure-free (group B) for patients with at least 12-months follow-up postsurgery. Full-scale intelligence quotient (FSIQ) was used as a measure of cognitive outcome.

Results: Eighty-six males and 64 females were identified. Median presurgical FSIQ was 81. One hundred twenty-one patients (80.5%) underwent surgery. Median follow-up after surgery was 2 years, with 92 patients (76%) having at least 12 months of follow-up after surgery. Seventy-four patients (80%) were seizure-free, and 18 (20%) continued to have seizures. Radiologically demonstrated complete tumor resection was associated with higher rates of seizure freedom (P = .026). Higher presurgical FSIQ was related to shorter epilepsy duration until surgery (P = .012) and to older age at seizure onset (P = .043).

Significance: A high proportion of children who present with epilepsy and GNTs go on to have surgical tumor resection with excellent postoperative seizure control. Complete resection is associated with a higher chance of seizure freedom. Higher presurgical cognitive functioning is associated with shorter duration of epilepsy prior to surgery and with older age at seizure onset. Given the high rate of eventual surgery, early surgical intervention should be considered in children with continuing seizures associated with GNTs.
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http://dx.doi.org/10.1111/epi.13961DOI Listing
January 2018

Seizure outcome after corpus callosotomy in a large paediatric series.

Dev Med Child Neurol 2018 02 23;60(2):199-206. Epub 2017 Oct 23.

Department of Neurosurgery, Great Ormond Street Hospital for Children, London, UK.

Aim: To describe 20 years of experience with corpus callosotomy at Great Ormond Street Hospital for Children, London and the Children's Hospital at Westmead, Sydney.

Method: Records of patients who underwent corpus callosotomy between January 1995 and December 2015 were reviewed. Complications of surgery and changes in seizure type and frequency, injuries, and use of antiepileptic drugs were recorded. Drop attacks were analysed using Kaplan-Meier event-free survival curves. Multivariable regression analysis was used to assess the effect of clinical characteristics on outcome at last follow-up.

Results: Inclusion criteria were met for 55 patients younger than 18 years of age. Median follow-up length was 36 months. At the last follow-up, 26 out of 55 patients (47%) had rare or no drop attacks. In those without a good outcome at final follow-up, 26 out of 29 (90%) had drop attacks return within 12 months of surgery. There were no preoperative predictors of developing drop attacks postoperatively. The median number of antiepileptic drugs significantly reduced from three to two. Transient neurological complications were experienced by 11 out of 55 patients (20%) and 6 out of 55 patients had surgical complications (11%).

Interpretation: Corpus callosotomy is a well-tolerated procedure that is effective at reducing the severity of drop attacks in paediatric patients. Drop attacks that do return are likely to do so within 12 months and the number of antiepileptic drugs can be significantly reduced.

What This Paper Adds: Corpus callosotomy is an effective palliative treatment and well tolerated in children. Good outcomes for the first 12 months after surgery were likely to continue. The number of antiepileptic drugs can be significantly reduced after corpus callosotomy. Patients with fewer than three types of seizure had better outcomes. There were fewer injuries from drop attacks after surgery.
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http://dx.doi.org/10.1111/dmcn.13592DOI Listing
February 2018

Corpus callosotomy outcomes in pediatric patients: A systematic review.

Epilepsia 2016 07 29;57(7):1053-68. Epub 2016 May 29.

Faculty of Medicine, The University of Sydney, Sydney, New South Wales, Australia.

Objective: Corpus callosotomy is a palliative neurosurgical treatment for patients with either generalized or multifocal refractory epilepsy and injurious drop attacks. This report aims to systematically review the pediatric literature.

Methods: Medline, Embase, Web of Knowledge, and Scopus were searched systematically for published articles on treatment outcomes of corpus callosotomy for refractory epilepsy. Studies were included if the patient population was younger than 18 at the time of surgery and median follow-up was >1 year. Studies were excluded if resective surgery was also performed.

Results: A total of 12 articles met inclusion criteria. All articles were retrospective case series, with the exception of one being a prospectively designed retrospective case series. There was very little agreement among authors on the definition of a good seizure outcome. Articles that used the Engel classification found that 88.2% of total corpus callosotomy patients had a worthwhile reduction in seizures compared with 58.6% of patients who underwent anterior corpus callosotomy (p < 0.05). Drop attacks improved from corpus callosotomy more than other generalized seizure types. Reported complications were minor in all but one patient, and one death was reported. Transient disconnection syndrome was significantly more likely in total corpus callosotomy than in anterior corpus callosotomy (12.5% vs. 0%; p < 0.05). Improvements in quality of life, behavior, and intelligence/development quotient, as well as parental satisfaction, were generally correlated with seizure outcome. There was no postcallosotomy change in the number of antiepileptic drugs.

Significance: Total corpus callosotomy was significantly more likely to result in a reduction in seizures. Anterior corpus callosotomy was unlikely to result in disconnection syndrome. Although all of the papers drew a similar conclusion, the quality of evidence was low. At best, the evidence raises the hypothesis that corpus callosotomy is a safe and effective treatment for refractory generalized epilepsy. It is clear that a case-control or randomized trial is warranted.
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http://dx.doi.org/10.1111/epi.13408DOI Listing
July 2016

Response.

J Neurosurg Pediatr 2016 Jan;17(1):117-8

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January 2016

Congenital spinal dermal tract: how accurate is clinical and radiological evaluation?

J Neurosurg Pediatr 2015 Jun 13;15(6):651-6. Epub 2015 Mar 13.

Department of Neurosurgery, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.

OBJECT A dermal sinus tract is a common form of occult spinal dysraphism. The presumed etiology relates to a focal failure of disjunction resulting in a persistent adhesion between the neural and cutaneous ectoderm. Clinical and radiological features can appear innocuous, leading to delayed diagnosis and failure to appreciate the implications or extent of the abnormality. If it is left untreated, complications can include meningitis, spinal abscess, and inclusion cyst formation. The authors present their experience in 74 pediatric cases of spinal dermal tract in an attempt to identify which clinical and radiological factors are associated with an infective presentation and to assess the reliability of MRI in evaluating this entity. METHODS Consecutive cases of spinal dermal tract treated with resection between 1998 and 2010 were identified from the departmental surgical database. Demographics, clinical history, and radiological and operative findings were collected from the patient records. The presence or absence of active infection (abscess, meningitis) at the time of neurosurgical presentation and any history of local sinus discharge or infection was assessed. Magnetic resonance images were reviewed to evaluate the extent of the sinus tract and determine the presence of an inclusion cyst. Radiological and operative findings were compared. RESULTS The surgical course was uncomplicated in 90% of 74 cases eligible for analysis. Magnetic resonance imaging underreported the presence of both an intradural tract (MRI 46%, operative finding 86%) and an intraspinal inclusion cyst (MRI 15%, operative finding 24%). A history of sinus discharge (OR 12.8, p = 0.0003) and the intraoperative identification of intraspinal inclusion cysts (OR 5.6, p = 0.023) were associated with an infective presentation. There was no significant association between the presence of an intradural tract discovered at surgery and an infective presentation. CONCLUSIONS Surgery for the treatment of spinal dermal tract carries a low morbidity. While it seems intuitive that tracts without intradural extension carry a low risk of spinal cord tethering, it is not possible to reliably detect these cases using MRI. Similarly, intraspinal dermoid cannot be reliably excluded using MRI and carries an increased risk of infection. These points justify excision together with intradural exploration of all spinal dermal sinus tracts.
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http://dx.doi.org/10.3171/2014.11.PEDS14341DOI Listing
June 2015

COL4A1 mutations should not be a contraindication for epilepsy surgery.

Childs Nerv Syst 2014 Aug 27;30(8):1467-9. Epub 2014 May 27.

Paediatric Neurology Department, Great Ormond Street Hospital, Great Ormond Street, London, WC1N 3JH, UK,

Purpose: We describe the first case in the literature of complication-free epilepsy surgery in a paediatric patient with collagen type IV alpha 1 (COL4A1) mutation.

Methods: This is a case report.

Results: COL4A1 mutations disrupt the integrity of vascular basement membranes, so predisposing to a broad spectrum of disorders including periventricular leucomalacia, haemorrhagic stroke, aneurysm formation, epilepsy and developmental delay. Intracranial haemorrhage is reported and may be recurrent or associated with trauma and anticoagulant therapy. Children have an increased risk of stroke with general anaesthesia. A 6-year-old girl, COL4A1 mutation positive, had drug-resistant epilepsy, cerebral palsy and developmental delay. Following presurgical evaluation, she was a candidate for corpus callosotomy. Previous general anaesthesia had been uncomplicated. Preoperative full blood count and coagulation studies were normal. Perioperatively, normotension was maintained, and anticoagulation was avoided. A complete corpus callosotomy was performed with no intracranial haemorrhage or other perioperative complications.

Conclusion: Although there is an increased risk of intracranial haemorrhages in COL4A1 patients, this is not clearly quantifiable. There are minimal data in the literature on the subject. COL4A1 mutations should not be a contraindication for presurgical evaluation. Each patient should be individually evaluated and assessed, risks and benefits were carefully weighed, and informed decisions were reached after thorough discussions with patients and families.
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http://dx.doi.org/10.1007/s00381-014-2440-5DOI Listing
August 2014

The prognostic value of brain extracellular fluid nitric oxide metabolites after traumatic brain injury.

Neurocrit Care 2013 Aug;19(1):65-8

Department of Neuroanaesthesia, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.

Background: Nitric oxide (NO) is a compound with both protective and damaging effects on neurons. Quantification of NO metabolites in humans is limited by sample contamination with blood. In vivo cerebral microdialysis may offer an alternative approach as sampling of extracellular fluid (ECF) adjacent to neurons becomes possible. We investigate the prognostic value of brain ECF NO metabolites in patients with traumatic brain injury (TBI).

Methods: A prospective case cohort of 195 ECF samples collected from 11 cases over 4 days following TBI was collected. Nitrate and nitrite concentrations ([NO x ]) were quantified using a vanadium-based colorimetric assay.

Results: Early ECF [NO x ] (<48 h post TBI) were significantly higher in non-survivors (median 59.2 μmol/l, n = 7) compared to survivors (23.3 μmol/l, n = 4) (P = 0.04). Late (48-96 h) ECF [NO x ] remained higher in non-survivors (47.9 μmol/l) compared to survivors (23.0 μmol/l) but this was not significant (P = 0.29). Receiver operator characteristic analysis shows an optimized cutoff level for ECF [NO x ] of 26.5 μmol/l measured <48 h post TBI for predicting non-survival (sensitivity 100%, specificity 75%).

Conclusion: Early ECF NO x concentrations are of prognostic value after TBI. ECF NO x may be a useful biomarker for treatment trials targeted at nitric oxide metabolism.
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http://dx.doi.org/10.1007/s12028-011-9633-5DOI Listing
August 2013

Analysis of the changes in the oxidation of brain tissue cytochrome-c-oxidase in traumatic brain injury patients during hypercapnoea: a broadband NIRS study.

Adv Exp Med Biol 2011 ;701:9-14

Biomedical Optics Research Laboratory, Department of Medical Physics and Bioengineering, University College London, Gower Street, London WC1E 6BT, UK.

Using broadband near-infrared spectroscopy (NIRS) and cerebral microdialysis (MD),we investigated cerebral cellular metabolism and mitochondrial redox states, following hypercapnoea in 6 patients with traumatic brain injury (TBI). In all patients hypercapnoea increased intracranial pressure and cerebral blood flow velocity measured with transcranial Doppler. Despite the likely increase in cerebral oxygen delivery, we did not see an increase in the oxidation status of cytochrome-c-oxidase [oxCCO] in every patient. Analysis of the NIRS data demonstrated two patterns of the changes; Group A (n = 4) showed an increase in [oxCCO] of 0.34(± 0.34)µM and Group B (n = 2) a decrease of 0.40(± 0.41)µM. Although no obvious association was seen between the Δ[oxCCO] and the MD, measured changes in lactate and pyruvate concentrations. Further work using model informed data interpretation may be helpful in understanding the multimodal signals acquired in this heterogeneous patient group.
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http://dx.doi.org/10.1007/978-1-4419-7756-4_2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038017PMC
August 2011

In vivo monitoring of neuronal loss in traumatic brain injury: a microdialysis study.

Brain 2011 Feb;134(Pt 2):464-83

Department of Neuroimmunology, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.

Traumatic brain injury causes diffuse axonal injury and loss of cortical neurons. These features are well recognized histologically, but their in vivo monitoring remains challenging. In vivo cortical microdialysis samples the extracellular fluid adjacent to neurons and axons. Here, we describe a novel neuronal proteolytic pathway and demonstrate the exclusive neuro-axonal expression of Pavlov's enterokinase. Enterokinase is membrane bound and cleaves the neurofilament heavy chain at positions 476 and 986. Using a 100 kDa microdialysis cut-off membrane the two proteolytic breakdown products, extracellular fluid neurofilament heavy chains NfH(476-986) and NfH(476-1026), can be quantified with a relative recovery of 20%. In a prospective clinical in vivo study, we included 10 patients with traumatic brain injury with a median Glasgow Coma Score of 9, providing 640 cortical extracellular fluid samples for longitudinal data analysis. Following high-velocity impact traumatic brain injury, microdialysate extracellular fluid neurofilament heavy chain levels were significantly higher (6.18 ± 2.94 ng/ml) and detectable for longer (> 4 days) compared with traumatic brain injury secondary to falls (0.84 ± 1.77 ng/ml, < 2 days). During the initial 16 h following traumatic brain injury, strong correlations were found between extracellular fluid neurofilament heavy chain levels and physiological parameters (systemic blood pressure, anaerobic cerebral metabolism, excessive brain tissue oxygenation, elevated brain temperature). Finally, extracellular fluid neurofilament heavy chain levels were of prognostic value, predicting mortality with an odds ratio of 7.68 (confidence interval 2.15-27.46, P = 0.001). In conclusion, this study describes the discovery of Pavlov's enterokinase in the human brain, a novel neuronal proteolytic pathway that gives rise to specific protein biomarkers (NfH(476-986) and Nf(H476-1026)) applicable to in vivo monitoring of diffuse axonal injury and neuronal loss in traumatic brain injury.
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http://dx.doi.org/10.1093/brain/awq360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030768PMC
February 2011

The effect on cerebral tissue oxygenation index of changes in the concentrations of inspired oxygen and end-tidal carbon dioxide in healthy adult volunteers.

Anesth Analg 2009 Sep;109(3):906-13

Department of Neuroanaesthesia and Neurocritical Care, The National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, UK.

Background: A variety of near-infrared spectroscopy devices can be used to make noninvasive measurements of cerebral tissue oxygen saturation (ScO2). The ScO2 measured by the NIRO 300 spectrometer (Hamamatsu Photonics, Japan) is called the cerebral tissue oxygenation index (TOI) and is an assessment of the balance between cerebral oxygen delivery and utilization. We designed this study to investigate the effect of systemic and intracranial physiological changes on TOI.

Methods: Fifteen healthy volunteers were studied during isocapneic hyperoxia and hypoxemia, and normoxic hypercapnea and hypocapnea. Absolute cerebral TOI and changes in oxy- and deoxyhemoglobin concentrations were measured using a NIRO 300 spectrometer. Changes in arterial oxygen saturation (SaO2), ETCO2, heart rate, mean arterial blood pressure (MBP), and middle cerebral artery blood flow velocity (Vmca) were also measured during these physiological challenges. Changes in cerebral blood volume (CBV) were subsequently calculated from changes in total cerebral hemoglobin concentration.

Results: Baseline TOI was 67.3% with an interquartile range (IQR) of 65.2%-71.9%. Hypoxemia was associated with a median decrease in TOI of 7.1% (IQR -9.1% to -5.4%) from baseline (P < 0.0001) and hyperoxia with a median increase of 2.3% (IQR 2.0%-2.5%) (P < 0.0001). Hypocapnea caused a reduction in TOI of 2.1% (IQR -3.3% to -1.3%) from baseline (P < 0.0001) and hypercapnea an increase of 2.6% (IQR 1.4%-3.7%) (P < 0.0001). Changes in SaO2 (P < 0.0001), ETCO2 (P < 0.0001), CBV (P = 0.0003), and MBP (P = 0.03) were significant variables affecting TOI. Changes in Vmca (P = 0.7) and heart rate (P = 0.2) were not significant factors.

Conclusion: TOI is an easy-to-monitor variable that provides real-time, multisite, and noninvasive assessment of the balance between cerebral oxygen delivery and utilization. However, TOI is a complex variable that is affected by SaO2 and ETCO2, and, to a lesser extent, by MBP and CBV. Clinicians need to be aware of the systemic and cerebral physiological changes that can affect TOI to interpret changes in this variable during clinical monitoring.
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http://dx.doi.org/10.1213/ane.0b013e3181aedcdcDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2742623PMC
September 2009

Relationship between brain tissue haemodynamics, oxygenation and metabolism in the healthy human adult brain during hyperoxia and hypercapnea.

Adv Exp Med Biol 2009 ;645:315-20

Department of Medical Physics and Bioengineering, Malet Place Engineering Building, University College London, Gower Street, London WC1E 6BT, UK.

This study investigates the relationship between changes in brain tissue haemodynamics, oxygenation and oxidised cytochrome-c-oxidase ([oxCCO]) in the adult brain during hyperoxia and hypercapnea. 10 healthy volunteers were studied. We measured the mean blood flow velocity of the right middle cerebral artery (Vmca) with transcranial Doppler (TCD) and changes in concentrations of total haemoglobin ([HbT]=[HbO2]+[HHb]), haemoglobin difference ([Hbdiff]=[HbO2]-[HHb]) and [oxCCO] with broadband near-infrared spectroscopy (NIRS). We also measured the absolute tissue oxygenation index (TOI) using NIR spatially resolved spectroscopy. During hyperoxia there was an increase in TOI (2.33 +/- 0.29%), [Hbdiff] (4.57 +/- 1.27 microM) and in the oxidation of [oxCCO] (0.09 +/- 0.12 microM); but a reduction in Vmca (5.85 +/- 4.85%) and HbT (1.29 +/- 0.91 microM). During hyperoxia there was a positive correlation between [oxCCO] and TOI and [Hbdiff] (r=0.83 and r=0.95) and a negative association between [oxCCO] and Vmca and [HbT] (r=-0.74 and r=-0.87). During hypercapnea there was an increase in TOI (2.76 +/- 2.16%), [Hbdiff] (7.36 +/- 2.64), [HbT] (2.61 +/- 2.7 microM), Vmca (14.92 +/- 17.5%) and in the oxidation of [oxCCO] (0.25 +/- 0.17 microM). Correlation analysis shows that there was association between [oxCCO] and TOI, [Hbdiff] and [HbT] (r=0.83, r=0.93 and r=0.82) but not with Vmca (r=0.33). We conclude that an increase in [oxCCO] was seen during both challenges and it was highly associated with brain tissue oxygenation.
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http://dx.doi.org/10.1007/978-0-387-85998-9_47DOI Listing
March 2009

Estimating a modified Grubb's exponent in healthy human brains with near infrared spectroscopy and transcranial Doppler.

Physiol Meas 2009 Jan 27;30(1):1-12. Epub 2008 Nov 27.

Department of Medical Physics and Bioengineering, University College London, London, UK.

The relationship between cerebral blood volume (CBV) and flow (CBF) has been widely studied. One of the most significant early studies was by Grubb et al (1974 Stroke 5 630-9), who conducted hypercapnia studies in primates with positron emission tomography (PET) and empirically found CBV = 0.8 CBF(0.38). The exponent used here has since been known as the Grubb's exponent. In this paper, we define a similar exponent known as the modified Grubb's exponent, G', which is based on CBV and cerebral blood flow velocity (CBFV) estimated by near infrared spectroscopy (NIRS) and transcranial Doppler respectively, i.e. G' = log(CBV/CBV(0))/log(CBFV/CBFV(0)), where CBV(0) and CBFV(0) are baseline values. The aim of this study was to estimate the nominal value of the modified Grubb's exponent in healthy human brains. We conducted hypercapnia and hypocapnia studies on 14 healthy adult subjects. The correlation coefficient between log(CBV/CBV(0)) and log(CBFV/CBFV(0)) is 0.71 (p < 0.0001). We found a modified Grubb's exponent of 0.13 (the 95% confidence bounds are 0.10 and 0.17) which is expectedly lower than the conventional Grubb's exponents estimated by other techniques. The modified Grubb's exponent is a simple measure to quantify the hemodynamics between local CBV and global CBFV in the brain and as such may provide insight on brain physiology. Both NIRS and transcranial Doppler techniques are non-invasive and portable, facilitating future studies in other population groups such as brain-injured patients.
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http://dx.doi.org/10.1088/0967-3334/30/1/001DOI Listing
January 2009

Increase in cerebral aerobic metabolism by normobaric hyperoxia after traumatic brain injury.

J Neurosurg 2008 Sep;109(3):424-32

Department of Neuroanaesthesia and Neurocritical Care, The National Hospital for Neurology and Neurosurgery, UK.

Object: Traumatic brain injury (TBI) is associated with depressed aerobic metabolism and mitochondrial dysfunction. Normobaric hyperoxia (NBH) has been suggested as a treatment for TBI, but studies in humans have produced equivocal results. In this study the authors used brain tissue O(2) tension measurement, cerebral microdialysis, and near-infrared spectroscopy to study the effects of NBH after TBI. They investigated the effects on cellular and mitochondrial redox states measured by the brain tissue lactate/pyruvate ratio (LPR) and the change in oxidized cytochrome c oxidase (CCO) concentration, respectively.

Methods: The authors studied 8 adults with TBI within the first 48 hours postinjury. Inspired oxygen percentage at normobaric pressure was increased from baseline to 60% for 60 minutes and then to 100% for 60 minutes before being returned to baseline for 30 minutes.

Results: The results are presented as the median with the interquartile range in parentheses. During the 100% inspired oxygen percentage phase, brain tissue O2 tension increased by 7.2 kPa (range 4.5-9.6 kPa) (p < 0.0001), microdialysate lactate concentration decreased by 0.26 mmol/L (range 0.0-0.45 mmol/L) (p = 0.01), microdialysate LPR decreased by 1.6 (range 1.0-2.3) (p = 0.02), and change in oxidized CCO concentration increased by 0.21 mumol/L (0.13-0.38 micromol/L) (p = 0.0003). There were no significant changes in intracranial pressure or arterial or microdialysate glucose concentration. The change in oxidized CCO concentration correlated with changes in brain tissue O(2) tension (r(s)= 0.57, p = 0.005) and in LPR (r(s)= -0.53, p = 0.006).

Conclusions: The authors have demonstrated oxidation in cerebral cellular and mitochondrial redox states during NBH in adults with TBI. These findings are consistent with increased aerobic metabolism and suggest that NBH has the potential to improve outcome after TBI. Further studies are warranted.
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http://dx.doi.org/10.3171/JNS/2008/109/9/0424DOI Listing
September 2008

Cerebral tissue oxygen saturation calculated using low frequency haemoglobin oscillations measured by near infrared spectroscopy in adult ventilated patients.

Adv Exp Med Biol 2008 ;614:235-44

Department of Medical Physics and Bioengineering, University College London, London, UK.

Oxy- (HbO2) and deoxy- (HHb) haemoglobin signals measured by near infrared (NIR) spectroscopy over the human frontal lobes frequently contain respiratory and low frequency oscillations (LFOs). It has been suggested previously that venous oxygen saturation (SvO2) can be calculated from these respiratory oscillations. In this paper, we investigated the use of a Fourier transform based algorithm to calculate an oxygen saturation measure known as S(osc)O2 which may be a close estimate of the underlying SvO2. S(osc)O2 was calculated using three different frequency ranges, (1) respiratory oscillations only, (2) LFOs only, and (3) both respiratory oscillations and LFOs. At each frequency range S(osc)O2 was calculated using either (1) the modified Beer-Lambert law (MBL) or (2) spatially resolved spectroscopy (SRS). In total six different measurements of S(osc)O2 were investigated here. Experiments were performed in six adult ventilated patients with traumatic brain injury. The patients' inspired oxygen fraction (FiO2) was raised in two hyperoxic phases. The calculated S(osc)O2 values were compared with other cerebral oxygenation measures including an intraparenchymal catheter based brain tissue oxygen tension (PbrO2) and the NIR based tissue oxygenation index (TOI). It was found that the S(osc)O2 calculated using the combined respiratory and LFO frequency range and the SRS method resulted in the highest detection rates of hyperoxic changes. This measure of S(osc)O2 may provide a viable, continuous, non invasive, bedside measure of cerebral venous oxygen saturation.
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http://dx.doi.org/10.1007/978-0-387-74911-2_27DOI Listing
April 2008

Changes in the attenuation of near infrared spectra by the healthy adult brain during hypoxaemia cannot be accounted for solely by changes in the concentrations of oxy- and deoxy-haemoglobin.

Adv Exp Med Biol 2008 ;614:217-25

Department of Neuroanaesthesia and Neurocritical Care, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK.

It has been suggested that changes in oxidised cytochrome c oxidase concentration ([oxCCO]) measured using cerebral near infrared spectroscopy (NIRS) may be algorithm artefacts. We examine the change in near infrared (NIR) attenuation by the healthy adult brain (n = 10) during hypoxaemia. Broadband spectroscopic data were collected during normoxia, and hypoxaemia. The UCLn algorithm was used to fit (a) oxy- (HbO2) and deoxy-haemoglobin (HHb) spectra (2 component fit), and (b) HbO2, HHb and oxidised-reduced cytochrome c oxidase difference spectra (3 component fit) to the mean change in NIR attenuation between baseline and hypoxaemia. The sum of squares of the residuals was 100 x 10(-7) OD2 for the 2 component fit and 8 x 10(-7) OD2 for the 3 component fit, and the two sets of residuals differed from each other (p = 0.0003). We compare experimental and simulated data and suggest that the 2 component residuals indicate a change in [oxCCO]. Changes in near infrared attenuation by the healthy adult brain during hypoxaemia cannot be accounted for solely by changes in oxy- and deoxy-haemoglobin concentrations. Including [oxCCO] in the algorithm improves its fit quality. These data suggest that changes in cerebral cytochrome c oxidase redox occur during hypoxaemia and that they can be detected using NIRS.
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http://dx.doi.org/10.1007/978-0-387-74911-2_25DOI Listing
April 2008

Investigation of frontal cortex, motor cortex and systemic haemodynamic changes during anagram solving.

Adv Exp Med Biol 2008 ;614:21-8

Department of Medical Physics and Bioengineering, Malet Place Engineering Building, Gower Street, University College London, London, UK WC1E 6BT.

We have previously reported changes in the concentrations of oxy-(delta[HbO2]) deoxy- (delta[HHb]) and total haemoglobin (delta[HbT] = delta[HbO2] + delta[HHb]) measured using near infrared spectroscopy (NIRS) over the frontal cortex (FC) during an anagram solving task. These changes were associated with a significant increase in both mean blood pressure (MBP) and heart rate (HR). The aim of this study was to investigate whether the changes in MBP previously recorded during an anagram solving task produces associated changes in scalp blood flow (flux) measured by laser Doppler and whether any changes are seen in NIRS haemodynamic measurements over a control region of the brain (motor cortex: MC). During the 4-Letter anagram task significant changes were observed in the delta[HbO2], delta[HHb] and delta[HbT] in both the frontal and motor cortex (n = 11, FC p < 0.01, MC p < 0.01). These changes were accompanied by significant changes in both MBP (n = 11, p < 0.01) and scalp flux (n = 9, p = 0.01). During the 7-Letter anagram task significant changes were observed in the delta[HbO2] and delta[HbT] (n = 11, FC p < 0.01, MC p < 0.01), which were accompanied by significant changes in both MBP (n = 11, p = 0.05) and flux (n = 9, p = 0.05). The task-related changes seen in MBP and flux in this study appear to contribute to the changes in the NIRS signals over both the activated and control regions of the cortex.
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http://dx.doi.org/10.1007/978-0-387-74911-2_3DOI Listing
April 2008

Near-infrared spectroscopic quantification of changes in the concentration of oxidized cytochrome c oxidase in the healthy human brain during hypoxemia.

J Biomed Opt 2007 Mar-Apr;12(2):024002

The National Hospital for Neurology and Neurosurgery, Department of Neuroanaesthesia and Neurocritical Care, Queen Square, London WC1N 3BG, United Kingdom.

The near-IR cytochrome c oxidase (CCO) signal has potential as a clinical marker of changes in mitochondrial oxygen utilization. We examine the CCO signal response to reduced oxygen delivery in the healthy human brain. We induced a reduction in arterial oxygen saturation from baseline levels to 80% in eight healthy adult humans, while minimizing changes in end tidal carbon dioxide tension. We measured changes in the cerebral concentrations of oxidized CCO (Delta[oxCCO]), oxyhemoglobin (Delta[HbO(2)]), and deoxyhemoglobin (Delta[HHb]) using broadband near-IR spectroscopy (NIRS), and estimated changes in cerebral oxygen delivery (ecDO(2)) using pulse oximetry and transcranial Doppler ultrasonography. Results are presented as median (interquartile range). At the nadir of hypoxemia ecDO(2) decreased by 9.2 (5.4 to 12.1)% (p<0.0001), Delta[oxCCO] decreased by 0.24 (0.06 to 0.28) micromoles/l (p<0.01), total hemoglobin concentration increased by 2.83 (2.27 to 4.46) micromoles/l (p<0.0001), and change in hemoglobin difference concentration (Delta[Hbdiff]=Delta[HbO(2)]-Delta[HHb]) decreased by 12.72 (11.32 to 16.34) micromoles/l (p<0.0001). Change in ecDO(2) correlated with Delta[oxCCO] (r=0.78, p<0.001), but not with either change in total hemoglobin concentration or Delta[Hbdiff]. This is the first description of cerebral Delta[oxCCO] during hypoxemia in healthy adults. Studies are ongoing to investigate the clinical relevance of this signal in patients with traumatic brain injury.
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http://dx.doi.org/10.1117/1.2718541DOI Listing
July 2007