Dopaminergic brainstem disconnection is common to pharmacological and pathological consciousness perturbation.

Clinical research into consciousness has long focused on cortical macroscopic networks and their disruption in pathological or pharmacological consciousness perturbation. Despite demonstrating diagnostic utility in disorders of consciousness (DoC) and monitoring anesthetic depth, these cortico-centric approaches have been unable to characterize which neurochemical systems may underpin consciousness alterations. Instead, preclinical experiments have long implicated the dopaminergic ventral tegmental area (VTA) in the brainstem. Despite dopaminergic agonist efficacy in DoC patients equally pointing to dopamine, the VTA has not been studied in human perturbed consciousness. To bridge this translational gap between preclinical subcortical and clinical cortico-centric perspectives, we assessed functional connectivity changes of a histologically characterized VTA using functional MRI recordings of pharmacologically (propofol sedation) and pathologically perturbed consciousness (DoC patients). Both cohorts demonstrated VTA disconnection from the precuneus and posterior cingulate (PCu/PCC), a main default mode network node widely implicated in consciousness. Strikingly, the stronger VTA-PCu/PCC connectivity was, the more the PCu/PCC functional connectome resembled its awake configuration, suggesting a possible neuromodulatory relationship. VTA-PCu/PCC connectivity increased toward healthy control levels only in DoC patients who behaviorally improved at follow-up assessment. To test whether VTA-PCu/PCC connectivity can be affected by a dopaminergic agonist, we demonstrated in a separate set of traumatic brain injury patients without DoC that methylphenidate significantly increased this connectivity. Together, our results characterize an in vivo dopaminergic connectivity deficit common to reversible and chronic consciousness perturbation. This noninvasive assessment of the dopaminergic system bridges preclinical and clinical work, associating dopaminergic VTA function with macroscopic network alterations, thereby elucidating a critical aspect of brainstem-cortical interplay for consciousness.

Neural correlates of different behavioral response to transcranial direct current stimulation between patients in the unresponsive wakefulness syndrome and minimally conscious state.

In this study, we used event-related potential (ERP) and 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) to study the neural correlates of different behavioral response to transcranial direct current stimulation (tDCS) between patients in unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS). Thirteen patients (eight in UWS and five in MCS) underwent 20 anodal tDCS sessions of the left dorsolateral prefrontal cortex (DLPFC). Before tDCS, all the patients and six age-matched healthy subjects underwent a cerebral FDG-PET scan and ERP test. The coma recovery scale-revised (CRS-R) results revealed that after tDCS, a significant improvement was observed only in the MCS group. The ERP results supported that MCS patients preserved more high-order cortical information processing capacities. The residual brain metabolism in the left DLPFC in MCS patients supported that a residual brain activity in the stimulated area was necessary for a behavioral response to tDCS. Our study also demonstrated that the cerebral metabolic rates of glucose (CMRgl) ratios in intrinsic network were correlated significantly with CRS-R in MCS patients. In addition, the right prefrontal region might be another potential therapeutic target for MCS patients.

Brain networks predict metabolism, diagnosis and prognosis at the bedside in disorders of consciousness.

Recent advances in functional neuroimaging have demonstrated novel potential for informing diagnosis and prognosis in the unresponsive wakeful syndrome and minimally conscious states. However, these technologies come with considerable expense and difficulty, limiting the possibility of wider clinical application in patients. Here, we show that high density electroencephalography, collected from 104 patients measured at rest, can provide valuable information about brain connectivity that correlates with behaviour and functional neuroimaging. Using graph theory, we visualize and quantify spectral connectivity estimated from electroencephalography as a dense brain network. Our findings demonstrate that key quantitative metrics of these networks correlate with the continuum of behavioural recovery in patients, ranging from those diagnosed as unresponsive, through those who have emerged from minimally conscious, to the fully conscious locked-in syndrome. In particular, a network metric indexing the presence of densely interconnected central hubs of connectivity discriminated behavioural consciousness with accuracy comparable to that achieved by expert assessment with positron emission tomography. We also show that this metric correlates strongly with brain metabolism. Further, with classification analysis, we predict the behavioural diagnosis, brain metabolism and 1-year clinical outcome of individual patients. Finally, we demonstrate that assessments of brain networks show robust connectivity in patients diagnosed as unresponsive by clinical consensus, but later rediagnosed as minimally conscious with the Coma Recovery Scale-Revised. Classification analysis of their brain network identified each of these misdiagnosed patients as minimally conscious, corroborating their behavioural diagnoses. If deployed at the bedside in the clinical context, such network measurements could complement systematic behavioural assessment and help reduce the high misdiagnosis rate reported in these patients. These metrics could also identify patients in whom further assessment is warranted using neuroimaging or conventional clinical evaluation. Finally, by providing objective characterization of states of consciousness, repeated assessments of network metrics could help track individual patients longitudinally, and also assess their neural responses to therapeutic and pharmacological interventions.

Investigation of UCH-L1 levels in ischemic stroke, intracranial hemorrhage and metabolic disorder induced impaired consciousness.

OBJECTIVE: We aimed to determine the levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) in patients admitted to the emergency department with impaired consciousness due to metabolic or neurological reasons. MATERIALS - METHODS: The study included 80 patients with ischemic stroke (IS), 40 patients with intracranial hemorrhage (ICH), 80 patients with metabolic disorder induced impaired consciousness (MDIC) and 40 healthy controls. RESULTS: The levels of UCH-L1 [median (IQR)] were as follows: 5.59ng/mL (3.90-9.37) in IS, 5.44ng/ml (4.01-13.98) in ICH, 3.34ng/ml (2.29-5.88) in MDIC and 3.94ng/ml (3.31-7.95) in healthy volunteers. Significantly higher levels were detected in IS and ICH than in MDIC and healthy volunteers. In ROC curve analysis, we detected 63.75% sensitivity and 62.5% specificity (AUC=0.626, p<0.0199, 95% CI: 0.533-0.713) with a cutoff value of 4.336ng/ml for IS and 75% sensitivity and 55% specificity (AUC=0.664, p<0.0071, 95% CI: 0.549-0.766) with a cut-off value of 4.036ng/ml for ICH. However, the sensitivity and specificity for MDIC was 36.25% and 77.5%, respectively, with a cut-off value of 3.256ng/ml (AUC=0.525, p=0.6521, 95% CI: 0.432-0.617). UCH-L1 levels were found to increase significantly with increasing time between the onset of symptoms and blood sampling (r=0.345, p<0.001). However, no correlation was found between UCH-L1 levels and age (r=0.014, p=0.833), GCS (r=-0.115, p=0.074), mRS (r=0.063, p=0.475) and NIHSS (r=0.056, p=0.520). CONCLUSION: In this study, we detected significantly higher levels of UCH-L1 in patients with IS and ICH compared to patients with MDIC and healthy volunteers.

Cerebral oxygen saturation monitoring in pediatric altered mental status patients.

OBJECTIVES: A pilot study assessing the potential utility of cerebral oximetry (local cerebral oxygen saturation [rcSO2]) in children presenting to the emergency department (ED) with altered mental status (AMS) and no history of trauma. METHODS: Patients who presented to a tertiary pediatric ED with AMS were monitored with left and right cerebral near-infrared spectroscopy probes and the first 30 minutes of rcSO2 data was analyzed. Patients with a history of trauma were excluded. Patients with an abnormal head computed tomography (CT) (n = 146) were compared with those with a negative head CT (n = 45). RESULTS: Mean rcSO2 values were consistent during each time period studied (5, 10, 20, and 30 minutes). In this study population, rcSO2 less than 50% or greater than 80% and increased absolute difference between the left and right rcSO2 measurements were associated with an abnormal CT scan. A difference of 12.2% between the left and right rcSO2 values had a 100% positive predictive value for an abnormal head CT among our patients. Cumulative graphical plots of rcSO2 trends showed that values <50% were associated with subdural hematomas (SDH) and values >80% were associated with epidural hematomas (EDH). CONCLUSIONS: This study demonstrated that cerebral oximetry can noninvasively detect altered cerebral physiology among a selected patient population. The difference between the left and right rcSO2 readings most reliably identified those subjects with altered cerebral physiology. In the future, rcSO2 monitoring has the potential to be used as a screening tool to identify, localize, and characterize intracranial injuries among children with AMS without a history of trauma.

The neurological wake-up test does not alter cerebral energy metabolism and oxygenation in patients with severe traumatic brain injury.

BACKGROUND: The neurological wake-up test (NWT) is used to monitor the level of consciousness in patients with traumatic brain injury (TBI). However, it requires interruption of sedation and may elicit a stress response. We evaluated the effects of the NWT using cerebral microdialysis (MD), brain tissue oxygenation (PbtiO2), jugular venous oxygen saturation (SjvO2), and/or arterial-venous difference (AVD) for glucose, lactate, and oxygen in patients with severe TBI. METHODS: Seventeen intubated TBI patients (age 16-74 years) were sedated using continuous propofol infusion. All patients received intracranial pressure (ICP) and cerebral perfusion pressure (CPP) monitoring in addition to MD, PbtiO2 and/or SjvO2. Up to 10 days post-injury, ICP, CPP, PbtiO2 (51 NWTs), MD (49 NWTs), and/or SjvO2 (18 NWTs) levels during propofol sedation (baseline) and NWT were compared. MD was evaluated at a flow rate of 1.0 µL/min (28 NWTs) or the routine 0.3 µL/min rate (21 NWTs). RESULTS: The NWT increased ICP and CPP levels (p < 0.05). Compared to baseline, interstitial levels of glucose, lactate, pyruvate, glutamate, glycerol, and the lactate/pyruvate ratio were unaltered by the NWT. Pathological SjvO2 (<50 % or >71 %; n = 2 NWTs) and PbtiO2 (<10 mmHg; n = 3 NWTs) values were rare at baseline and did not change following NWT. Finally, the NWT did not alter the AVD of glucose, lactate, or oxygen. CONCLUSIONS: The NWT-induced stress response resulted in increased ICP and CPP levels although it did not negatively alter focal neurochemistry or cerebral oxygenation in TBI patients.

Whole brain modelling for simulating pharmacological interventions on patients with disorders of consciousness.

Disorders of consciousness (DoC) represent a challenging and complex group of neurological conditions characterised by profound disturbances in consciousness. The current range of treatments for DoC is limited. This has sparked growing interest in developing new treatments, including the use of psychedelic drugs. Nevertheless, clinical investigations and the mechanisms behind them are methodologically and ethically constrained. To tackle these limitations, we combined biologically plausible whole-brain models with deep learning techniques to characterise the low-dimensional space of DoC patients. We investigated the effects of model pharmacological interventions by including the whole-brain dynamical consequences of the enhanced neuromodulatory level of different neurotransmitters, and providing geometrical interpretation in the low-dimensional space. Our findings show that serotonergic and opioid receptors effectively shifted the DoC models towards a dynamical behaviour associated with a healthier state, and that these improvements correlated with the mean density of the activated receptors throughout the brain. These findings mark an important step towards the development of treatments not only for DoC but also for a broader spectrum of brain diseases. Our method offers a promising avenue for exploring the therapeutic potential of pharmacological interventions within the ethical and methodological confines of clinical research.

Diagnostic value of PET imaging in clinically unresponsive patients.

Rapid advancements in the critical care management of acute brain injuries have facilitated the survival of numerous patients who may have otherwise succumbed to their injuries. The probability of conscious recovery hinges on the extent of structural brain damage and the level of metabolic and functional cerebral impairment, which remain challenging to assess via laboratory, clinical, or functional tests. Current research settings and guidelines highlight the potential value of fluorodeoxyglucose-PET (FDG-PET) for diagnostic and prognostic purposes, emphasizing its capacity to consistently illustrate a metabolic reduction in cerebral glucose uptake across various disorders of consciousness. Crucially, FDG-PET might be a pivotal tool for differentiating between patients in the minimally conscious state and those in the unresponsive wakefulness syndrome, a persistent clinical challenge. In patients with disorders of consciousness, PET offers utility in evaluating the degree and spread of functional disruption, as well as identifying irreversible neural damage. Further, studies that capture responses to external stimuli can shed light on residual or revived brain functioning. Nevertheless, the validity of these findings in predicting clinical outcomes calls for additional long-term studies with larger patient cohorts suffering from consciousness impairment. Misdiagnosis of conscious illnesses during bedside clinical assessments remains a significant concern. Based on the clinical research settings, current clinical guidelines recommend PET for diagnostic and/or prognostic purposes. This review article discusses the clinical categories of conscious disorders and the diagnostic and prognostic value of PET imaging in clinically unresponsive patients, considering the known limitations of PET imaging in such contexts.

Cerebral electrometabolic coupling in disordered and normal states of consciousness.

We assess cerebral integrity with cortical and subcortical FDG-PET and cortical electroencephalography (EEG) within the mesocircuit model framework in patients with disorders of consciousness (DoCs). The mesocircuit hypothesis proposes that subcortical activation facilitates cortical function. We find that the metabolic balance of subcortical mesocircuit areas is informative for diagnosis and is associated with four EEG-based power spectral density patterns, cortical metabolism, and α power in healthy controls and patients with a DoC. Last, regional electrometabolic coupling at the cortical level can be identified in the θ and α ranges, showing positive and negative relations with glucose uptake, respectively. This relation is inverted in patients with a DoC, potentially related to altered orchestration of neural activity, and may underlie suboptimal excitability states in patients with a DoC. By understanding the neurobiological basis of the pathophysiology underlying DoCs, we foresee translational value for diagnosis and treatment of patients with a DoC.

Lysergic acid diethylamide differentially modulates the reticular thalamus, mediodorsal thalamus, and infralimbic prefrontal cortex: An in vivo electrophysiology study in male mice.

BACKGROUND: The reticular thalamus gates thalamocortical information flow via finely tuned inhibition of thalamocortical cells in the mediodorsal thalamus. Brain imaging studies in humans show that the psychedelic lysergic acid diethylamide (LSD) modulates activity and connectivity within the cortico-striato-thalamo-cortical (CSTC) circuit, altering consciousness. However, the electrophysiological effects of LSD on the neurons in these brain areas remain elusive. METHODS: We employed in vivo extracellular single-unit recordings in anesthetized adult male mice to investigate the dose-response effects of cumulative LSD doses (5-160 µg/kg, intraperitoneal) upon reticular thalamus GABAergic neurons, thalamocortical relay neurons of the mediodorsal thalamus, and pyramidal neurons of the infralimbic prefrontal cortex. RESULTS: LSD decreased spontaneous firing and burst-firing activity in 50% of the recorded reticular thalamus neurons in a dose-response fashion starting at 10 µg/kg. Another population of neurons (50%) increased firing and burst-firing activity starting at 40 µg/kg. This modulation was accompanied by an increase in firing and burst-firing activity of thalamocortical neurons in the mediodorsal thalamus. On the contrary, LSD excited infralimbic prefrontal cortex pyramidal neurons only at the highest dose tested (160 µg/kg). The dopamine D2 receptor (D2) antagonist haloperidol administered after LSD increased burst-firing activity in the reticular thalamus neurons inhibited by LSD, decreased firing and burst-firing activity in the mediodorsal thalamus, and showed a trend towards further increasing the firing activity of neurons of the infralimbic prefrontal cortex. CONCLUSION: LSD modulates firing and burst-firing activity of reticular thalamus neurons and disinhibits mediodorsal thalamus relay neurons at least partially in a D2-mediated fashion. These effects of LSD on thalamocortical gating could explain its consciousness-altering effects in humans.

Temporal patterns of interstitial pyruvate and amino acids after subarachnoid haemorrhage are related to the level of consciousness--a clinical microdialysis study.

BACKGROUND: Temporal patterns of brain interstitial amino acids after subarachnoid haemorrhage (SAH) were studied in relation to energy metabolite levels and to the severity of the initial global ischaemia as reflected by the level of consciousness at admission. METHOD: Intracerebral microdialysis was used to measure brain interstitial amino acids and the energy metabolites glucose, lactate, and pyruvate during five days in 19 patients. Patients who were conscious (n = 11) were compared to those who were unconscious on admission (n = 8). FINDINGS: Eight non-transmitter amino acids (alanine, asparagine, glutamine, isoleucine, leucine, phenylalanine, serine and tyrosine), as well as glycine and pyruvate showed a pattern of increasing concentrations starting at 60-70 h after the onset of SAH. The conscious patients showed more pronounced elevations of non-transmitter amino acids, glycine, taurine and pyruvate compared to the unconscious patient group. Pyruvate levels were initially critically low for all patients, then normalised in the conscious patients but remained low in the unconscious group. CONCLUSIONS: There was an increase of the cerebral interstitial levels of non-transmitter amino acids and glycine which correlated temporally to pyruvate levels, more pronounced in patients conscious on admission. Pyruvate levels in these patients normalised, but remained reduced in the unconscious patients. The increase of the non-transmitter amino acids and glycine could reflect an increased amino acid turnover in an attempt at repairing the injured brain, which could have been hampered by the lower pyruvate levels. Interstitial pyruvate may be a useful marker of the energy metabolic situation in the acutely injured brain.

[Receptor antagonist of NMDA and animal models of schizophrenia].

Schizophrenia is one of the common mental diseases. Because the mechanism of the schizophrenia is significantly complicated, the cause is still unknown. N-methyl-D-aspartate receptor antagonist can simulate the positive and negative symptoms, as well as the cognitive disorder of schizophrenia. Thus it has been widely used to establish the animal models of schizophrenia. The relationship of the three blocking agents of ion channels (phencyclidine, MK-801, ketamine) and the establishment of schizophrenia animal models is reviewed in this article.

Interhemispherical Anatomical Disconnection in Disorders of Consciousness Patients.

In patients with disorder of consciousness (DOC), the corpus callosum (CC) and subcortical white matter (SWM) integrity were shown to discriminate between diagnostic categories. The aims of the study were: (1) to clarify the link between the integrity of CC and of SWM and the clinical status in DOC patients, disentangling the role played by the different brain injuries (traumatic or hemorrhagic brain injury); (2) to investigate the relationship between the CC integrity and the brain metabolism. We assessed the diagnostic accuracy of the CC and SWM integrity, using diffusion tensor imaging (DTI) and structural magnetic resonance imaging (sMRI), in a sample of DOC individuals, well balanced for diagnosis and etiology. The CC DTI-derived measures were correlated with the brain metabolism, computed with fluorodeoxyglucose positron emission tomography. Our results showed that the CC macrostructural DTI-derived measures discriminate between diagnosis and correlate with the clinical status of DOC patients irrespective of the etiology. Moreover, the CC DTI-derived measures strongly correlate with the metabolism of the right hemisphere. No significant diagnostic accuracy emerged for the CC sMRI evaluation and the SWM measures. Our results indicate that: (1) the degree of the interhemispherical anatomical disconnection is a marker of the level of consciousness independent from the type of brain injury; (2) CC alterations might be the consequence of the reduced brain metabolism. Remarkably, our results suggest that the functional interplay between the two hemispheres is linked tightly to the level of consciousness.

Alterations in Brain Metabolites in Patients with Epilepsy with Impaired Consciousness: A Case-Control Study of Interictal Multivoxel 1H-MRS Findings.

BACKGROUND AND PURPOSE: Previous studies have shown perfusion abnormalities in the thalamus and upper brain stem in patients with epilepsy with impaired consciousness. We hypothesized that these areas associated with consciousness will also show metabolic abnormalities. However, metabolic abnormalities in those areas correlated with consciousness has not been characterized with multiple-voxel 1H-MRS. In this study, we investigated the metabolic alterations in these brain regions and assessed the correlation between seizure features and metabolic alterations. MATERIALS AND METHODS: Fifty-seven patients with epilepsy and 24 control subjects underwent routine MR imaging and 3D multiple-voxel 1H-MRS. Patients were divided into 3 subgroups: focal impaired awareness seizures (n = 18), primary generalized tonic-clonic seizures (n = 19), and secondary generalized tonic-clonic seizures (n = 20). The measured metabolite alterations in NAA/Cr, NAA/(Cr + Cho), and Cho/Cr ratios in brain regions associated with the consciousness network were compared between the patient and control groups. ROIs were placed in the bilateral inferior frontal gyrus, supramarginal gyrus, cingulate gyrus, precuneus, thalamus, and upper brain stem. Correlations between clinical parameters (epilepsy duration and seizure frequency) and metabolite alterations were analyzed. RESULTS: Significantly lower NAA/Cr and NAA/(Cho + Cr) ratios (P < .05 and < .01, respectively) were observed in the bilateral thalamus and upper brain stem in all experimental groups, and significantly high Cho/Cr ratios (P < .05) were observed in the right thalamus in the focal impaired awareness seizures group. There were no significant differences in metabolite ratios among the 3 patient groups (P > .05). The secondary generalized tonic-clonic seizures group showed a negative correlation between the duration of epilepsy and the NAA/(Cr + Cho) ratio in the bilateral thalamus (P < .05). CONCLUSIONS: Metabolic alterations were observed in the brain stem and thalamus in patients with epilepsy with impaired consciousness.

Cellular stress and AMPK links metformin and diverse compounds with accelerated emergence from anesthesia and potential recovery from disorders of consciousness.

The neural correlates of consciousness and the mechanisms by which general anesthesia (GA) modulate such correlates to induce loss of consciousness (LOC) has been described as one of the biggest mysteries of modern medicine. Several cellular targets and neural circuits have been identified that play a critical role in LOC induced by GA, including the GABAA receptor and ascending arousal nuclei located in the basal forebrain, hypothalamus, and brain stem. General anesthetics (GAs) including propofol and inhalational agents induce LOC in part by potentiating chloride influx through the GABAA receptor, leading to neural inhibition and LOC. Interestingly, nearly all GAs used clinically may also induce paradoxical excitation, a phenomenon in which GAs promote neuronal excitation at low doses before inducing unconsciousness. Additionally, emergence from GA, a passive process that occurs after anesthetic removal, is associated with lower anesthetic concentrations in the brain compared to doses associated with induction of GA. AMPK, an evolutionarily conserved kinase activated by cellular stress (e.g. increases in calcium [Ca2+] and/or reactive oxygen species [ROS], etc.) increases lifespan and healthspan in several model organisms. AMPK is located throughout the mammalian brain, including in neurons of the thalamus, hypothalamus, and striatum as well as in pyramidal neurons in the hippocampus and cortex. Increases in ROS and Ca2+ play critical roles in neuronal excitation and glutamate, the primary excitatory neurotransmitter in the human brain, activates AMPK in cortical neurons. Nearly every neurotransmitter released from ascending arousal circuits that promote wakefulness, arousal, and consciousness activates AMPK, including acetylcholine, histamine, orexin-A, dopamine, and norepinephrine. Several GAs that are commonly used to induce LOC in human patients also activate AMPK (e.g. propofol, sevoflurane, isoflurane, dexmedetomidine, ketamine, midazolam). Various compounds that accelerate emergence from anesthesia, thus mitigating problematic effects associated with delayed emergence such as delirium, also activate AMPK (e.g. nicotine, caffeine, forskolin, carbachol). GAs and neurotransmitters also act as preconditioning agents and the GABAA receptor inhibitor bicuculline, which reverses propofol anesthesia, also activates AMPK in cortical neurons. We propose the novel hypothesis that cellular stress-induced AMPK activation links wakefulness, arousal, and consciousness with paradoxical excitation and accelerated emergence from anesthesia. Because AMPK activators including metformin and nicotine promote proliferation and differentiation of neural stem cells located in the subventricular zone and the dentate gyrus, AMPK activation may also enhance brain repair and promote potential recovery from disorders of consciousness (i.e. minimally conscious state, vegetative state, coma).

Influence of inter-stimulus interval of spinal cord stimulation in patients with disorders of consciousness: A preliminary functional near-infrared spectroscopy study.

Spinal cord stimulation (SCS) is a promising treatment for disorders of consciousness (DOC), but the underlying mechanism and most effective procedures remain uncertain. To optimize the protocol, previous studies evaluated the frequency-specific effects of SCS on neurophysiological activities. However, whether and how the inter-stimulus interval (ISI) parameter affects the SCS neuromodulation in DOC remains unknown. We enrolled nine DOC patients who had implanted SCS devices and conducted three different durations of ISIs. Using functional near-infrared spectroscopy (fNIRS), we monitored the blood volume fluctuations in the prefrontal and occipital cortices during the SCS. The results showed that short stimuli (30 s) induced significant cerebral blood volume changes, especially in the prefrontal cortex, an important area in the consciousness system. By comparing the mean value of the responses from the first and the last block in each session, a shorter ISI was found to improve the blood volume in the prefrontal cortex. This phenomenon was more significant for the subgroup of patients with a favorable prognosis. These preliminary results imply that the ISI may be an important factor for SCS. The research paradigm proposed here also provides insights for further quantitative evaluations of the therapeutic effects of neuromodulation.

Early risk factors for mortality in children with seizure and/or impaired consciousness accompanied by fever without known etiology.

BACKGROUND: Children who present with seizure and/or impaired consciousness accompanied by fever without known etiology (SICF) may be diagnosed with either acute encephalopathy (AE) or febrile seizure (FS). Although approximately 5% of AE cases are fatal, it is difficult to identify fatal cases among children with SICF, which are often critical by the time of diagnosis. Thus, early prediction of outcomes for children with SICF, prior to diagnosis, may help to reduce mortality associated with AE. The aim of the present study was to identify clinical and laboratory risk factors for mortality acquired within 6 h of onset among children with SICF. METHODS: We retrospectively reviewed the medical records of children who had been admitted to Kobe Children's Hospital (Kobe, Japan) with SICF between October 2002 and September 2015. We compared clinical and laboratory characteristics acquired within 6 h of onset and outcomes between survivors and non-survivors using univariate and multivariate analyses. RESULTS: The survivor and non-survivor groups included 659 and nine patients, respectively. All patients in the non-survivor group received a final diagnosis of AE. Univariate analysis revealed significant differences between the groups with regard to seizure duration and the following laboratory parameters: aspartate transaminase (AST), alanine aminotransferase, lactate dehydrogenase, sodium, and lactate. The multivariate analysis identified AST as a significant independent factor associated with mortality. CONCLUSIONS: Elevation of AST within 6 h of onset is independently correlated with mortality in children with SICF. Our result may elucidate earlier intervention for patients with high risk of mortality.

Cerebral proton magnetic resonance spectroscopy in children with diabetic ketoacidosis.

BACKGROUND AND PURPOSE: Subclinical cerebral edema occurs in many, if not most, children with diabetic ketoacidosis (DKA) and may be an indicator of subtle brain injury. Brain ratios of N-acetylaspartate (NAA) to creatine (Cr), measured by proton MR spectroscopy, decrease with neuronal injury or dysfunction. We hypothesized that brain NAA/Cr ratios may be decreased in children in DKA, indicating subtle neuronal injury. MATERIALS AND METHODS: Twenty-nine children with DKA underwent cerebral proton MR spectroscopy during DKA treatment (2-12 hours after initiating therapy) and after recovery from the episode (72 hours or more after the initiation of therapy). We measured peak heights of NAA, Cr, and choline (Cho) in 3 locations within the brain: the occipital gray matter, the basal ganglia, and periaqueductal gray matter. These regions were identified in previous studies as areas at greater risk for neurologic injury in DKA-related cerebral edema. We calculated the ratios of NAA/Cr and Cho/Cr and compared these ratios during the acute illness and recovery periods. RESULTS: In the basal ganglia, the ratio of NAA/Cr was significantly lower during DKA treatment compared with that after recovery (1.68 +/- 0.24 versus 1.86 +/- 0.28, P<.005). There was a trend toward lower NAA/Cr ratios during DKA treatment in the periaqueductal gray matter (1.66 +/- 0.38 versus 1.91 +/- 0.50, P=.06) and the occipital gray matter (1.97 +/- 0.28 versus 2.13 +/- 0.18, P=.08). In contrast, there were no significant changes in Cho/Cr ratios in any region. CONCLUSIONS: NAA/Cr ratios are decreased in children during DKA and improve after recovery. This finding suggests that during DKA neuronal function or viability or both are compromised and improve after treatment and recovery.

Comparison of analytical methods of brain [18F]FDG-PET after severe traumatic brain injury.

BACKGROUND: Loss of consciousness has been shown to reduce cerebral metabolic rates of glucose (CMRglc) measured by brain [18F]FDG-PET. Measurements of regional metabolic patterns by normalization to global cerebral metabolism or cerebellum may underestimate widespread reductions. NEW METHOD: The aim of this study was to compare quantification methods of whole brain glucose metabolism, including whole brain [18F]FDG uptake normalized to uptake in cerebellum, normalized to injected activity, normalized to plasma tracer concentration, and two methods for estimating CMRglc. Six patients suffering from severe traumatic brain injury (TBI) and ten healthy controls (HC) underwent a 10min static [18F]FDG-PET scan and venous blood sampling. RESULTS: Except from normalizing to cerebellum, all quantification methods found significant lower level of whole brain glucose metabolism of 25-33% in TBI patients compared to HC. In accordance these measurements correlated to level of consciousness. COMPARISON WITH EXISTING METHODS: Our study demonstrates that the analysis method of the [18F]FDG PET data has a substantial impact on the estimated whole brain cerebral glucose metabolism in patients with severe TBI. Importantly, the SUVR method which is often used in a clinical setting was not able to distinguish patients with severe TBI from HC at the whole-brain level. CONCLUSION: We recommend supplementing a static [18F]FDG scan with a single venous blood sample in future studies of patients with severe TBI or reduced level of consciousness. This can be used for simple semi-quantitative uptake values by normalizing brain activity uptake to plasma tracer concentration, or quantitative estimates of CMRglc.