Cerebral Hemodynamic and Metabolic Abnormalities in Neonatal Hypocalcemia: Findings from Advanced MRI.

BACKGROUND AND PURPOSE: Neonatal hypocalcemia is the most common metabolic disorder, and whether asymptomatic disease should be treated with calcium supplements remains controversial. We aimed to quantify neonatal hypocalcemia's global CBF and cerebral metabolic rate of oxygen (CMRO2) using physiologic MR imaging and elucidate the pathophysiologic vulnerabilities of neonatal hypocalcemia. MATERIALS AND METHODS: A total of 37 consecutive patients with neonatal hypocalcemia were enrolled. They were further divided into subgroups with and without structural MR imaging abnormalities, denoted as neonatal hypocalcemia-a (n = 24) and neonatal hypocalcemia-n (n = 13). Nineteen healthy neonates were enrolled as a control group. Brain physiologic parameters determined using phase-contrast MR imaging, T2-relaxation-under-spin-tagging MR imaging, and brain volume were compared between patients with neonatal hypocalcemia (their subgroups) and controls. Predictors for neonatal hypocalcemia-related brain injuries were identified using multivariate logistic regression analysis and expressed as ORs with 95% CIs. RESULTS: Patients with neonatal hypocalcemia showed significantly lower CBF and CMRO2 compared with controls. Furthermore, the neonatal hypocalcemia-a subset (versus controls or neonatal hypocalcemia-n) had significantly lower CBF and CMRO2. There was no obvious difference in CBF and CMRO2 between the neonatal hypocalcemia-n subset and controls. CBF and CMRO2 were independently associated with neonatal hypocalcemia. The ORs were 0.80 (95% CI, 0.65-0.99) and 0.97 (95% CI, 0.89-1.05) for CBF and CMRO2, respectively. CONCLUSIONS: Neonatal hypocalcemia with structural damage may exhibit lower hemodynamics and cerebral metabolism. CBF may be useful in assessing the need for calcium supplementation in asymptomatic neonatal hypocalcemia to prevent brain injury.

Metabolic modulation of synaptic failure and thalamocortical hypersynchronization with preserved consciousness in Glut1 deficiency.

Individuals with glucose transporter type I deficiency (G1D) habitually experience nutrient-responsive epilepsy associated with decreased brain glucose. However, the mechanistic association between blood glucose concentration and brain excitability in the context of G1D remains to be elucidated. Electroencephalography (EEG) in G1D individuals revealed nutrition time-dependent seizure oscillations often associated with preserved volition despite electrographic generalization and uniform average oscillation duration and periodicity, suggesting increased facilitation of an underlying neural loop circuit. Nonlinear EEG ictal source localization analysis and simultaneous EEG/functional magnetic resonance imaging converged on the thalamus-sensorimotor cortex as one potential circuit, and 18F-deoxyglucose positron emission tomography (18F-DG-PET) illustrated decreased glucose accumulation in this circuit. This pattern, reflected in a decreased thalamic to striatal 18F signal ratio, can aid with the PET imaging diagnosis of the disorder, whereas the absence of noticeable ictal behavioral changes challenges the postulated requirement for normal thalamocortical activity during consciousness. In G1D mice, 18F-DG-PET and mass spectrometry also revealed decreased brain glucose and glycogen, but preserved tricarboxylic acid cycle intermediates, indicating no overall energy metabolism failure. In brain slices from these animals, synaptic inhibition of cortical pyramidal neurons and thalamic relay neurons was decreased, and neuronal disinhibition was mitigated by metabolic sources of carbon; tonic-clonic seizures were also suppressed by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor inhibition. These results pose G1D as a thalamocortical synaptic disinhibition disease associated with increased glucose-dependent neuronal excitability, possibly in relation to reduced glycogen. Together with findings in other metabolic defects, inhibitory neuron dysfunction is emerging as a modulable mechanism of hyperexcitability.

Potential Audiological and MRI Markers of Tinnitus.

BACKGROUND: Subjective tinnitus, or ringing sensation in the ear, is a common disorder with no accepted objective diagnostic markers. PURPOSE: The purpose of this study was to identify possible objective markers of tinnitus by combining audiological and imaging-based techniques. RESEARCH DESIGN: Case-control studies. STUDY SAMPLE: Twenty adults drawn from our audiology clinic served as participants. The tinnitus group consisted of ten participants with chronic bilateral constant tinnitus, and the control group consisted of ten participants with no history of tinnitus. Each participant with tinnitus was closely matched with a control participant on the basis of age, gender, and hearing thresholds. DATA COLLECTION AND ANALYSES: Data acquisition focused on systematic administration and evaluation of various audiological tests, including auditory-evoked potentials (AEP) and otoacoustic emissions, and magnetic resonance imaging (MRI) tests. A total of 14 objective test measures (predictors) obtained from audiological and MRI tests were subjected to statistical analyses to identify the best predictors of tinnitus group membership. The least absolute shrinkage and selection operator technique for feature extraction, supplemented by the leave-one-out cross-validation technique, were used to extract the best predictors. This approach provided a conservative model that was highly regularized with its error within 1 standard error of the minimum. RESULTS: The model selected increased frontal cortex (FC) functional MRI activity to pure tones matching their respective tinnitus pitch, and augmented AEP wave N1 amplitude growth in the tinnitus group as the top two predictors of tinnitus group membership. These findings suggest that the amplified responses to acoustic signals and hyperactivity in attention regions of the brain may be a result of overattention among individuals that experience chronic tinnitus. CONCLUSIONS: These results suggest that increased functional MRI activity in the FC to sounds and augmented N1 amplitude growth may potentially be the objective diagnostic indicators of tinnitus. However, due to the small sample size and lack of subgroups within the tinnitus population in this study, more research is needed before generalizing these findings.

Triheptanoin for glucose transporter type I deficiency (G1D): modulation of human ictogenesis, cerebral metabolic rate, and cognitive indices by a food supplement.

IMPORTANCE: Disorders of brain metabolism are multiform in their mechanisms and manifestations, many of which remain insufficiently understood and are thus similarly treated. Glucose transporter type I deficiency (G1D) is commonly associated with seizures and with electrographic spike-waves. The G1D syndrome has long been attributed to energy (ie, adenosine triphosphate synthetic) failure such as that consequent to tricarboxylic acid (TCA) cycle intermediate depletion. Indeed, glucose and other substrates generate TCAs via anaplerosis. However, TCAs are preserved in murine G1D, rendering energy-failure inferences premature and suggesting a different hypothesis, also grounded on our work, that consumption of alternate TCA precursors is stimulated and may be detrimental. Second, common ketogenic diets lead to a therapeutically counterintuitive reduction in blood glucose available to the G1D brain and prove ineffective in one-third of patients. OBJECTIVE: To identify the most helpful outcomes for treatment evaluation and to uphold (rather than diminish) blood glucose concentration and stimulate the TCA cycle, including anaplerosis, in G1D using the medium-chain, food-grade triglyceride triheptanoin. DESIGN, SETTING, AND PARTICIPANTS: Unsponsored, open-label cases series conducted in an academic setting. Fourteen children and adults with G1D who were not receiving a ketogenic diet were selected on a first-come, first-enrolled basis. INTERVENTION: Supplementation of the regular diet with food-grade triheptanoin. MAIN OUTCOMES AND MEASURES: First, we show that, regardless of electroencephalographic spike-waves, most seizures are rarely visible, such that perceptions by patients or others are inadequate for treatment evaluation. Thus, we used quantitative electroencephalographic, neuropsychological, blood analytical, and magnetic resonance imaging cerebral metabolic rate measurements. RESULTS: One participant (7%) did not manifest spike-waves; however, spike-waves promptly decreased by 70% (P = .001) in the other participants after consumption of triheptanoin. In addition, the neuropsychological performance and cerebral metabolic rate increased in most patients. Eleven patients (78%) had no adverse effects after prolonged use of triheptanoin. Three patients (21%) experienced gastrointestinal symptoms, and 1 (7%) discontinued the use of triheptanoin. CONCLUSIONS AND RELEVANCE: Triheptanoin can favorably influence cardinal aspects of neural function in G1D. In addition, our outcome measures constitute an important framework for the evaluation of therapies for encephalopathies associated with impaired intermediary metabolism.