Pharmacological management of post-traumatic seizures in adults: current practice patterns in the UK and the Republic of Ireland.

BACKGROUND: Patient selection for seizure prophylaxis after traumatic brain injury (TBI) and duration of anti-epileptic drug treatment for patients with early post-traumatic seizures (PTS), remain plagued with uncertainty. In early 2017, a collaborative group of neurosurgeons, neurologists, neurointensive care and rehabilitation medicine physicians was formed in the UK with the aim of assessing variability in current practice and gauging the degree of uncertainty to inform the design of future studies. Here we present the results of a survey of clinicians managing patients with TBI in the UK and Ireland. MATERIALS AND METHODS: An online survey was developed and piloted. Following approval by the Academic Committee of the Society of British Neurological Surgeons, it was distributed via appropriate electronic mailing lists. RESULTS: One hundred and seventeen respondents answered the questionnaire, predominantly neurosurgeons (76%) from 30 (of 32) trauma-receiving hospitals in the UK and Ireland. Fifty-three percent of respondents do not routinely use seizure prophylaxis, but 38% prescribe prophylaxis for one week. Sixty percent feel there is uncertainty regarding the use of seizure prophylaxis, and 71% would participate in further research to address this question. Sixty-two percent of respondents use levetiracetam for treatment of seizures during the acute phase, and 42% continued for a total of 3 months. Overall, 90% were uncertain about the duration of treatment for seizures, and 78% would participate in further research to address this question. CONCLUSION: The survey results demonstrate the variation in practice and uncertainty in both described aspects of management of patients who have suffered a TBI. The majority of respondents would want to participate in future research to help try and address this critical issue, and this shows the importance and relevance of these two clinical questions.

Serum insulin-like growth factor-I levels are associated with improved white matter recovery after traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) is a common disabling condition with limited treatment options. Diffusion tensor imaging measures recovery of axonal injury in white matter (WM) tracts after TBI. Growth hormone deficiency (GHD) after TBI may impair axonal and neuropsychological recovery, and serum insulin-like growth factor-I (IGF-I) may mediate this effect. We conducted a longitudinal study to determine the effects of baseline serum IGF-I concentrations on WM tract and neuropsychological recovery after TBI. METHODS: Thirty-nine adults after TBI (84.6% male, median age = 30.5 years, 87.2% moderate-severe, median time since TBI = 16.3 months, n = 4 with GHD) were scanned twice, 13.3 months (range = 12.1-14.9) apart, and 35 healthy controls were scanned once. Symptom and quality of life questionnaires and cognitive assessments were completed at both visits (n = 33). Our main outcome measure was fractional anisotropy (FA), a measure of WM tract integrity, in a priori regions of interest: splenium of corpus callosum (SPCC) and posterior limb of internal capsule (PLIC). RESULTS: At baseline, FA was reduced in many WM tracts including SPCC and PLIC following TBI compared to controls, indicating axonal injury, with longitudinal increases indicating axonal recovery. There was a significantly greater increase in SPCC FA over time in patients with serum IGF-I above versus below the median for age. Only the higher IGF-I group had significant improvements in immediate verbal memory recall over time. INTERPRETATION: WM recovery and memory improvements after TBI were greater in patients with higher serum IGF-I at baseline. These findings suggest that the growth hormone/IGF-I system may be a potential therapeutic target following TBI. Ann Neurol 2017;82:30-43.

Extrinsic and Intrinsic Brain Network Connectivity Maintains Cognition across the Lifespan Despite Accelerated Decay of Regional Brain Activation.

The maintenance of wellbeing across the lifespan depends on the preservation of cognitive function. We propose that successful cognitive aging is determined by interactions both within and between large-scale functional brain networks. Such connectivity can be estimated from task-free functional magnetic resonance imaging (fMRI), also known as resting-state fMRI (rs-fMRI). However, common correlational methods are confounded by age-related changes in the neurovascular signaling. To estimate network interactions at the neuronal rather than vascular level, we used generative models that specified both the neural interactions and a flexible neurovascular forward model. The networks' parameters were optimized to explain the spectral dynamics of rs-fMRI data in 602 healthy human adults from population-based cohorts who were approximately uniformly distributed between 18 and 88 years (www.cam-can.com). We assessed directed connectivity within and between three key large-scale networks: the salience network, dorsal attention network, and default mode network. We found that age influences connectivity both within and between these networks, over and above the effects on neurovascular coupling. Canonical correlation analysis revealed that the relationship between network connectivity and cognitive function was age-dependent: cognitive performance relied on neural dynamics more strongly in older adults. These effects were driven partly by reduced stability of neural activity within all networks, as expressed by an accelerated decay of neural information. Our findings suggest that the balance of excitatory connectivity between networks, and the stability of intrinsic neural representations within networks, changes with age. The cognitive function of older adults becomes increasingly dependent on these factors. SIGNIFICANCE STATEMENT: Maintaining cognitive function is critical to successful aging. To study the neural basis of cognitive function across the lifespan, we studied a large population-based cohort (n = 602, 18-88 years), separating neural connectivity from vascular components of fMRI signals. Cognitive ability was influenced by the strength of connection within and between functional brain networks, and this positive relationship increased with age. In older adults, there was more rapid decay of intrinsic neuronal activity in multiple regions of the brain networks, which related to cognitive performance. Our data demonstrate increased reliance on network flexibility to maintain cognitive function, in the presence of more rapid decay of neural activity. These insights will facilitate the development of new strategies to maintain cognitive ability.

Atomoxetine restores the response inhibition network in Parkinson's disease.

Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson's disease.

Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures.

Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinson's disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double-blind randomized three-way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinson's disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion-weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinson's disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave-one-out cross-validation (LOOCV) to predict patients' responses in terms of improved stopping efficiency. We identified two optimal models: (1) a "clinical" model that predicted the response of an individual patient with 77-79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion-weighted imaging scan; and (2) a "mechanistic" model that explained the behavioral response with 85% accuracy for each drug, using drug-induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinson's disease, the individual patient's response to each drug can be predicted using a pattern of clinical and neuroimaging features.

Prevalence and correlates of vitamin D deficiency in adults after traumatic brain injury.

OBJECTIVES: Traumatic brain injury (TBI) is a major cause of long-term disability with variable recovery. Preclinical studies suggest that vitamin D status influences the recovery after TBI. However, there is no published clinical data on links between vitamin D status and TBI outcomes. The aim was to determine the (i) prevalence of vitamin D deficiency/insufficiency, and associations of vitamin D status with (ii) demographic factors and TBI severity, and with (iii) cognitive function, symptoms and quality of life, in adults after TBI. DESIGN: Retrospective audit of patients seen between July 2009 and March 2015. Serum vitamin D (25-hydroxy-cholecalciferol) was categorized as deficient (<40 nmol/l), insufficient (40-70 nmol/l) or replete (>70 nmol/l). PATIENTS: A total of 353 adults seen in tertiary hospital clinic (75·4% lighter skinned, 74·8% male, age median 35·1 year, range 26·6-48·3 year), 0·3-56·5 months after TBI (74·5% moderate-severe). MEASUREMENTS: Serum vitamin D concentrations; Addenbrooke's Cognitive Examination (ACE-R), Beck Depression Inventory-II (BDI-II), SF-36 Quality of Life, Pittsburgh Sleep Quality Index. RESULTS: In total, 46·5% of patients after TBI had vitamin D deficiency and 80·2% insufficiency/deficiency. Patients with vitamin D deficiency had lower ACE-R scores than those of vitamin D replete (mean effect size ± SEM 4·5 ± 2·1, P = 0·034), and higher BDI-II scores than those of vitamin D insufficient (4·5 ± 1·6, P = 0·003), correcting for age, gender, time since TBI and TBI severity. There was no association between vitamin D status and markers of TBI severity, sleep or quality of life. CONCLUSION: Vitamin D deficiency is common in patients after TBI and associated with impaired cognitive function and more severe depressive symptoms.

Damage to the Salience Network and interactions with the Default Mode Network.

Interactions between the Salience Network (SN) and the Default Mode Network (DMN) are thought to be important for cognitive control. However, evidence for a causal relationship between the networks is limited. Previously, we have reported that traumatic damage to white matter tracts within the SN predicts abnormal DMN function. Here we investigate the effect of this damage on network interactions that accompany changing motor control. We initially used fMRI of the Stop Signal Task to study response inhibition in humans. In healthy subjects, functional connectivity (FC) between the right anterior insula (rAI), a key node of the SN, and the DMN transiently increased during stopping. This change in FC was not seen in a group of traumatic brain injury (TBI) patients with impaired cognitive control. Furthermore, the amount of SN tract damage negatively correlated with FC between the networks. We confirmed these findings in a second group of TBI patients. Here, switching rather than inhibiting a motor response: (1) was accompanied by a similar increase in network FC in healthy controls; (2) was not seen in TBI patients; and (3) tract damage after TBI again correlated with FC breakdown. This shows that coupling between the rAI and DMN increases with cognitive control and that damage within the SN impairs this dynamic network interaction. This work provides compelling evidence for a model of cognitive control where the SN is involved in the attentional capture of salient external stimuli and signals the DMN to reduce its activity when attention is externally focused.

The neural basis of impaired self-awareness after traumatic brain injury.

Self-awareness is commonly impaired after traumatic brain injury. This is an important clinical issue as awareness affects long-term outcome and limits attempts at rehabilitation. It can be investigated by studying how patients respond to their errors and monitor their performance on tasks. As awareness is thought to be an emergent property of network activity, we tested the hypothesis that impaired self-awareness is associated with abnormal brain network function. We investigated a group of subjects with traumatic brain injury (n = 63) split into low and high performance-monitoring groups based on their ability to recognize and correct their own errors. Brain network function was assessed using resting-state and event-related functional magnetic resonance imaging. This allowed us to investigate baseline network function, as well as the evoked response of networks to specific events including errors. The low performance-monitoring group underestimated their disability and showed broad attentional deficits. Neural activity within what has been termed the fronto-parietal control network was abnormal in patients with impaired self-awareness. The dorsal anterior cingulate cortex is a key part of this network that is involved in performance-monitoring. This region showed reduced functional connectivity to the rest of the fronto-parietal control network at 'rest'. In addition, the anterior insulae, which are normally tightly linked to the dorsal anterior cingulate cortex, showed increased activity following errors in the impaired group. Interestingly, the traumatic brain injury patient group with normal performance-monitoring showed abnormally high activation of the right middle frontal gyrus, putamen and caudate in response to errors. The impairment of self-awareness was not explained either by the location of focal brain injury, or the amount of traumatic axonal injury as demonstrated by diffusion tensor imaging. The results suggest that impairments of self-awareness after traumatic brain injury result from breakdown of functional interactions between nodes within the fronto-parietal control network.

Salience network integrity predicts default mode network function after traumatic brain injury.

Efficient behavior involves the coordinated activity of large-scale brain networks, but the way in which these networks interact is uncertain. One theory is that the salience network (SN)--which includes the anterior cingulate cortex, presupplementary motor area, and anterior insulae--regulates dynamic changes in other networks. If this is the case, then damage to the structural connectivity of the SN should disrupt the regulation of associated networks. To investigate this hypothesis, we studied a group of 57 patients with cognitive impairments following traumatic brain injury (TBI) and 25 control subjects using the stop-signal task. The pattern of brain activity associated with stop-signal task performance was studied by using functional MRI, and the structural integrity of network connections was quantified by using diffusion tensor imaging. Efficient inhibitory control was associated with rapid deactivation within parts of the default mode network (DMN), including the precuneus and posterior cingulate cortex. TBI patients showed a failure of DMN deactivation, which was associated with an impairment of inhibitory control. TBI frequently results in traumatic axonal injury, which can disconnect brain networks by damaging white matter tracts. The abnormality of DMN function was specifically predicted by the amount of white matter damage in the SN tract connecting the right anterior insulae to the presupplementary motor area and dorsal anterior cingulate cortex. The results provide evidence that structural integrity of the SN is necessary for the efficient regulation of activity in the DMN, and that a failure of this regulation leads to inefficient cognitive control.

Cognitive control and the salience network: an investigation of error processing and effective connectivity.

The Salience Network (SN) consists of the dorsal anterior cingulate cortex (dACC) and bilateral insulae. The network responds to behaviorally salient events, and an important question is how its nodes interact. One theory is that the dACC provides the earliest cortical signal of behaviorally salient events, such as errors. Alternatively, the anterior right insula (aRI) has been proposed to provide an early cognitive control signal. As these regions frequently coactivate, it has been difficult to disentangle their roles using conventional methods. Here we use dynamic causal modeling and a Bayesian model evidence technique to investigate the causal relationships between nodes in the SN after errors. Thirty-five human subjects performed the Simon task. The task has two conditions (congruent and incongruent) producing two distinct error types. Neural activity associated with errors was investigated using fMRI. Subjects made a total of 1319 congruent and 1617 incongruent errors. Errors resulted in robust activation of the SN. Dynamic causal modeling analyses demonstrated that input into the SN was most likely via the aRI for both error types and that the aRI was the only region intrinsically connected to both other nodes. Only incongruent errors produced behavioral adaptation, and the strength of the connection between the dACC and the left insulae correlated with the extent of this behavioral change. We conclude that the aRI, not the dACC, drives the SN after errors on an attentionally demanding task, and that a change in the effective connectivity of the dACC is associated with behavioral adaptation after errors.

Individual prediction of white matter injury following traumatic brain injury.

OBJECTIVE: Traumatic brain injury (TBI) often results in traumatic axonal injury (TAI). This can be difficult to identify using conventional imaging. Diffusion tensor imaging (DTI) offers a method of assessing axonal damage in vivo, but has previously mainly been used to investigate groups of patients. Machine learning techniques are increasingly used to improve diagnosis based on complex imaging measures. We investigated whether machine learning applied to DTI data can be used to diagnose white matter damage after TBI and to predict neuropsychological outcome in individual patients. METHODS: We trained pattern classifiers to predict the presence of white matter damage in 25 TBI patients with microbleed evidence of TAI compared to neurologically healthy age-matched controls. We then applied these classifiers to 35 additional patients with no conventional imaging evidence of TAI. Finally, we used regression analyses to predict indices of neuropsychological outcome for information processing speed, executive function, and associative memory in a group of 70 heterogeneous patients. RESULTS: The classifiers discriminated between patients with microbleeds and age-matched controls with a high degree of accuracy, and outperformed other methods. When the trained classifiers were applied to patients without microbleeds, patients having likely TAI showed evidence of greater cognitive impairment in information processing speed and executive function. The classifiers were also able to predict the extent of impairments in information processing speed and executive function. INTERPRETATION: The work provides a proof of principle that multivariate techniques can be used with DTI to provide diagnostic information about clinically significant TAI.

Pituitary dysfunction after blast traumatic brain injury: The UK BIOSAP study.

OBJECTIVE: Pituitary dysfunction is a recognized consequence of traumatic brain injury (TBI) that causes cognitive, psychological, and metabolic impairment. Hormone replacement offers a therapeutic opportunity. Blast TBI (bTBI) from improvised explosive devices is commonly seen in soldiers returning from recent conflicts. We investigated: (1) the prevalence and consequences of pituitary dysfunction following moderate to severe bTBI and (2) whether it is associated with particular patterns of brain injury. METHODS: Nineteen male soldiers with moderate to severe bTBI (median age = 28.3 years) and 39 male controls with moderate to severe nonblast TBI (nbTBI; median age = 32.3 years) underwent full dynamic endocrine assessment between 2 and 48 months after injury. In addition, soldiers had structural brain magnetic resonance imaging, including diffusion tensor imaging (DTI), and cognitive assessment. RESULTS: Six of 19 (32.0%) soldiers with bTBI, but only 1 of 39 (2.6%) nbTBI controls, had anterior pituitary dysfunction (p = 0.004). Two soldiers had hyperprolactinemia, 2 had growth hormone (GH) deficiency, 1 had adrenocorticotropic hormone (ACTH) deficiency, and 1 had combined GH/ACTH/gonadotrophin deficiency. DTI measures of white matter structure showed greater traumatic axonal injury in the cerebellum and corpus callosum in those soldiers with pituitary dysfunction than in those without. Soldiers with pituitary dysfunction after bTBI also had a higher prevalence of skull/facial fractures and worse cognitive function. Four soldiers (21.1%) commenced hormone replacement(s) for hypopituitarism. INTERPRETATION: We reveal a high prevalence of anterior pituitary dysfunction in soldiers suffering moderate to severe bTBI, which was more frequent than in a matched group of civilian moderate to severe nbTBI subjects. We recommend that all patients with moderate to severe bTBI should routinely have comprehensive assessment of endocrine function.

Cerebral venous system and anatomical predisposition to high-altitude headache.

OBJECTIVE: As inspired oxygen availability falls with ascent to altitude, some individuals develop high-altitude headache (HAH). We postulated that HAH results when hypoxia-associated increases in cerebral blood flow occur in the context of restricted venous drainage, and is worsened when cerebral compliance is reduced. We explored this hypothesis in 3 studies. METHODS: In high-altitude studies, retinal venous distension (RVD) was ophthalmoscopically assessed in 24 subjects (6 female) and sea-level cranial magnetic resonance imaging was performed in 12 subjects ascending to 5,300m. Correlation of headache burden (summed severity scores [0-4]≤24 hours from arrival at each altitude) with RVD, and with cerebral/cerebrospinal fluid (CSF)/venous compartment volumes, was sought. In a sea-level hypoxic study, 11 subjects underwent gadolinium-enhanced magnetic resonance venography before and during hypoxic challenge (fraction of inspired oxygen=0.11, 1 hour). RESULTS: In the high-altitude studies, headache burden correlated with both RVD (Spearman rho=0.55, p=0.005) and with the degree of narrowing of 1 or both transverse venous sinuses (r=-0.56, p=0.03). It also related inversely to both the lateral+third ventricle summed volumes (Spearman rho=-0.5, p=0.05) and pericerebellar CSF volume (r=-0.56, p=0.03). In the hypoxic study, cerebral and retinal vein engorgement were correlated, and rose as the combined conduit score fell (a measure of venous outflow restriction; r=-0.66, p<0.05 and r=-0.75, p<0.05, respectively). INTERPRETATION: Arterial hypoxemia is associated with cerebral and retinal venous distension, whose magnitude correlates with HAH burden. Restriction in cerebral venous outflow is associated with retinal distension and HAH. Limitations in cerebral venous efferent flow may predispose to headache when hypoxia-related increases in cerebral arterial flow occur.

Distinct frontal networks are involved in adapting to internally and externally signaled errors.

Errors trigger changes in behavior that help individuals adapt to new situations. The dorsal anterior cingulate cortex (dACC) is thought to be central to this response, but more lateral frontal regions are also activated by errors and may make distinct contributions. We investigated error processing by studying 2 distinct error types: commission and timing. Thirty-five subjects performed a version of the Simon Task designed to produce large number of errors. Commission errors were internally recognized and were not accompanied by explicit feedback. In contrast, timing errors were difficult to monitor internally and were explicitly signaled. Both types of error triggered changes in behavior consistent with increased cognitive control. As expected, robust activation within the dACC and bilateral anterior insulae (the Salience Network) was seen for commission errors. In contrast, timing errors were not associated with activation of this network but did activate a bilateral network that included the right ventral attentional system. Common activation for both error types occurred within the pars operculari and angular gyri. These results show that the dACC does not respond to all behaviorally salient errors. Instead, the error-processing system is multifaceted, and control can be triggered independently of the dACC when feedback is unexpected.

Design, implementation and practice of JBEI-ICE: an open source biological part registry platform and tools.

The Joint BioEnergy Institute Inventory of Composable Elements (JBEI-ICEs) is an open source registry platform for managing information about biological parts. It is capable of recording information about 'legacy' parts, such as plasmids, microbial host strains and Arabidopsis seeds, as well as DNA parts in various assembly standards. ICE is built on the idea of a web of registries and thus provides strong support for distributed interconnected use. The information deposited in an ICE installation instance is accessible both via a web browser and through the web application programming interfaces, which allows automated access to parts via third-party programs. JBEI-ICE includes several useful web browser-based graphical applications for sequence annotation, manipulation and analysis that are also open source. As with open source software, users are encouraged to install, use and customize JBEI-ICE and its components for their particular purposes. As a web application programming interface, ICE provides well-developed parts storage functionality for other synthetic biology software projects. A public instance is available at public-registry.jbei.org, where users can try out features, upload parts or simply use it for their projects. The ICE software suite is available via Google Code, a hosting site for community-driven open source projects.

A rare presentation of rapidly progressing myopathy in an adolescent.

We present a case of severe juvenile dermatomyositis with limited response to steroids in an adolescent who developed symptoms within hours after receiving Pfizer BNT162b2 coronavirus disease 2019 vaccine. The patient presented with severe weakness of proximal muscles, dyspnoea, and tachycardia. His muscle enzymes were raised, and he was diagnosed with severe juvenile dermatomyositis following magnetic resonance imaging and muscle biopsy. His management was challenging, requiring multidisciplinary input, and difficult decisions with regard to the appropriate immunomodulatory treatments. The patient had to undergo escalating immunosuppressive treatments before he began to recover clinically and biochemically. To our knowledge, this is the first case in an adolescent although a few cases of similar presentations following coronavirus disease 2019 vaccination have been reported in adults. Elucidating the potential relationship of the vaccine with this severe myopathy in an adolescent is important for global vaccination policies, but avoiding the conflation of association with causation is also crucial in the context of the pandemic.

A robust method for investigating thalamic white matter tracts after traumatic brain injury.

Damage to the structural connections of the thalamus is a frequent feature of traumatic brain injury (TBI) and can be a key factor in determining clinical outcome. Until recently it has been difficult to quantify the extent of this damage in vivo. Diffusion tensor imaging (DTI) provides a validated method to investigate traumatic axonal injury, and can be applied to quantify damage to thalamic connections. DTI can also be used to assess white matter tract structure using tractography, and this technique has been used to study thalamo-cortical connections in the healthy brain. However, the presence of white matter injury can cause failure of tractography algorithms. Here, we report a method for investigating thalamo-cortical connectivity that bypasses the need for individual tractography. We first created a template for a number of thalamo-cortical connections using probabilistic tractography performed in ten healthy subjects. This template for investigating white matter structure was validated by comparison with individual tractography in the same group, as well as in an independent control group (N=11). We also evaluated two methods of masking tract location using the tract skeleton generated by tract based spatial statistics, and a cerebrospinal fluid mask. Voxel-wise estimates of fractional anisotropy derived from the template were more strongly correlated with individual tractography when both types of masking were used. The tract templates were then used to sample DTI measures from a group of TBI patients (N=22), with direct comparison performed against probabilistic tractography in individual patients. Probabilistic tractography often failed to produce anatomically plausible tracts in TBI patients. Importantly, we show that this problem increases as tracts become more damaged, and leads to underestimation of the amount of traumatic axonal injury. In contrast, the tract template can be used in these cases, allowing a more accurate assessment of white matter damage. In summary, we propose a method suitable for assessing specific thalamo-cortical white matter connections after TBI that is robust to the presence of varying amounts of traumatic axonal injury, as well as highlighting the potential problems of applying tractography algorithms in patient populations.

How can investigation of network function inform rehabilitation after traumatic brain injury?

PURPOSE OF REVIEW: Traumatic brain injury (TBI) often results in long-term cognitive impairments. This is often due to the disruption of brain networks that support cognition. Major advances have recently been made in our understanding of these networks. Here we review work that investigates the effect of TBI on brain networks, and discuss the potential importance of these findings for rehabilitation. RECENT FINDINGS: Large-scale brain networks, which we refer to as intrinsic connectivity networks (ICNs), have been identified. Traumatic axonal injury disrupts their white-matter connections, and altered brain activity within the networks is frequently observed after TBI. These changes relate to the pattern of cognitive impairment, and are useful for predicting clinical outcome. The effect of drugs such as methylphenidate, which can be used to augment rehabilitation, are beginning to be studied in the context of their effect on network function after TBI. SUMMARY: The assessment of brain network function after TBI provides insights into the pathophysiology of cognitive dysfunction and the mechanisms involved in recovery. These advances should provide the basis for a more detailed understanding of rehabilitation, and ultimately guide the development of targeted individualized therapy after TBI.

Production of the antimalarial drug precursor artemisinic acid in engineered yeast.

Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually. Disease control is hampered by the occurrence of multi-drug-resistant strains of the malaria parasite Plasmodium falciparum. Synthetic antimalarial drugs and malarial vaccines are currently being developed, but their efficacy against malaria awaits rigorous clinical testing. Artemisinin, a sesquiterpene lactone endoperoxide extracted from Artemisia annua L (family Asteraceae; commonly known as sweet wormwood), is highly effective against multi-drug-resistant Plasmodium spp., but is in short supply and unaffordable to most malaria sufferers. Although total synthesis of artemisinin is difficult and costly, the semi-synthesis of artemisinin or any derivative from microbially sourced artemisinic acid, its immediate precursor, could be a cost-effective, environmentally friendly, high-quality and reliable source of artemisinin. Here we report the engineering of Saccharomyces cerevisiae to produce high titres (up to 100 mg l(-1)) of artemisinic acid using an engineered mevalonate pathway, amorphadiene synthase, and a novel cytochrome P450 monooxygenase (CYP71AV1) from A. annua that performs a three-step oxidation of amorpha-4,11-diene to artemisinic acid. The synthesized artemisinic acid is transported out and retained on the outside of the engineered yeast, meaning that a simple and inexpensive purification process can be used to obtain the desired product. Although the engineered yeast is already capable of producing artemisinic acid at a significantly higher specific productivity than A. annua, yield optimization and industrial scale-up will be required to raise artemisinic acid production to a level high enough to reduce artemisinin combination therapies to significantly below their current prices.

Investigating white matter injury after mild traumatic brain injury.

PURPOSE OF REVIEW: Traumatic brain injury (TBI) often results in traumatic axonal injury (TAI). This is difficult to identify using conventional neuroimaging methods. We review recent work that uses advanced imaging methods to identify TAI following mild (m)TBI. RECENT FINDINGS: Susceptibility-weighted imaging (SWI) is a highly sensitive way of identifying microbleeds, which are a marker of TAI. Diffusion tensor imaging (DTI) provides a more flexible way of investigating white matter injury. Recent studies largely confirm that DTI is sensitive to white matter damage after mTBI. Distinct DTI abnormalities are observed in the acute and subacute/chronic stages. DTI measurements change dynamically after an injury, reflecting the evolving pathological processes. DTI abnormalities correlate with cognitive and neuropsychiatric impairments. Importantly, DTI can contribute to the prediction of clinical outcome and has begun to be applied to the study of sports and blast injury. SUMMARY: DTI and SWI are important advances in MRI that allow more detailed investigation of white matter injury. SWI is a highly sensitive way of identifying microbleeds. DTI is a flexible way of quantifying white matter integrity, and provides a method of diagnosing clinically significant white matter injury when conventional imaging is normal.