Corrigendum: A structural connectivity atlas of limbic brainstem nuclei.

[This corrects the article DOI: 10.3389/fnimg.2022.1009399.].

Optimization of Nutrition after Brain Injury: Mechanistic and Therapeutic Considerations.

Emerging science continues to establish the detrimental effects of malnutrition in acute neurological diseases such as traumatic brain injury, stroke, status epilepticus and anoxic brain injury. The primary pathological pathways responsible for secondary brain injury include neuroinflammation, catabolism, immune suppression and metabolic failure, and these are exacerbated by malnutrition. Given this, there is growing interest in novel nutritional interventions to promote neurological recovery after acute brain injury. In this review, we will describe how malnutrition impacts the biomolecular mechanisms of secondary brain injury in acute neurological disorders, and how nutritional status can be optimized in both pediatric and adult populations. We will further highlight emerging therapeutic approaches, including specialized diets that aim to resolve neuroinflammation, immunodeficiency and metabolic crisis, by providing pre-clinical and clinical evidence that their use promotes neurologic recovery. Using nutrition as a targeted treatment is appealing for several reasons that will be discussed. Given the high mortality and both short- and long-term morbidity associated with acute brain injuries, novel translational and clinical approaches are needed.

Brain Glutathione Increase and Seizure Burden Decrease in Patients with Intractable Epilepsy on Ketogenic Diet.

Background and Purpose: Ketogenic diet (KD) improves seizure control in patients with drug-resistant epilepsy. As increased mitochondrial levels of glutathione (GSH) might contribute to a change in seizure susceptibility, we quantified changes of absolute GSH levels in the brain by in vivo 1H magnetic resonance spectroscopy (1H MRS) and correlate that with degree of seizure control in patients on KD. Methods: Five cognitively normal adult patients with drug-resistant epilepsy were initially included and 2 completed the study. Each patient was evaluated by a neurologist and registered dietitian at baseline, 1, 3, and 6 months for seizure status and diet adherence after initiation of a modified atkins diet. Multiple metabolites including GSH were quantified using LCModel (version 6.3-1P; Stephen Provencher, Oakville, ON, CA) on a short echo time single-voxel 1H MRS in parieto/occipital grey matter and parietal white matter on a 3 Tesla General Electric magnet prior to starting the ketogenic diet and at 6 months. Results: Both patients (42-years-old male and 35-years-old female) demonstrated marked increases in absolute GSH level in both gray matter (0.12 to 1.40 and 0.10 to 0.70 international unit [IU]) and white matter (0.65 to 1.50 and 0.80 to 2.00 IU), as well as 50% improvements in seizure duration and frequency. Other metabolites including ketone bodies did not demonstrate consistent changes. Conclusions: Markedly increased levels of GSH (7-fold and 14-fold) were observed in longitudinal prospective study of two adult patients with intractable epilepsy with 50% seizure improvement after initiation of ketogenic diets. This pilot study supports the possible anticonvulsant role of GSH in the brain.

Results of a 2-week novel robotic rehabilitation program in 18 children with prior hemispherectomy.

BACKGROUND: Partial preservation of sensory and motor functions in the contralateral extremities after hemispherectomy is likely secondary to cortical reorganization of the remaining hemisphere and can be improved by rehabilitation. This study aims to investigate behavioral changes that may occur after a 2-week novel robotic rehabilitation program in 18 children with prior anatomic hemispherectomy. Other conventional rehabilitation methods were also reviewed and compared. METHODS: This study examined the impact of a novel robotic rehabilitation 2-week program on 18 hemispherectomy patients (average age 14.3 ± 3.9 years; age at hemispherectomy 5.6 ± 4.5 years). RESULTS: Statistically significant improvements were seen in the six-minute walk test (29 m, p < 0.001), Canadian Occupational Performance Measure performance (1.64 points, p = 0.002) and satisfaction (2.49 points, p = 0.001), and individual perceived performance on survey (1.72 points, p = 0.042). Fifteen patients showed improvement in the upper extremity Fugl-Meyer scores with an average increase of 3 points (p = 0.006). CONCLUSION: This study demonstrates clinically meaningful and statistically significant improvements in motor function and behavior following a novel robotic rehabilitation two-week program.

Cortical change after a 2-week novel robotic rehabilitation program in children with prior hemispherectomy: pilot imaging study.

INTRODUCTION: Partial preservation of sensory and motor functions in the contralateral extremities after hemispherectomy is likely secondary to cortical reorganization of the remaining hemisphere and can be improved by rehabilitation. This study aims to investigate behavioral and structural cerebral cortical changes that may occur after a 2-week novel robotic rehabilitation program in children with prior anatomic hemispherectomy. METHODS: Five patients with prior anatomic hemispherectomy (average age 10.8 years; all female) participated in a 2-week novel robotic rehabilitation program. Pre- and post-treatment (2 time points) high-resolution structural 3D FSPGR (fast spoiled gradient echo) magnetic resonance images were analyzed to measure cortical thickness and gray matter volume using a locally designed image processing pipeline. RESULTS: Four of the five patients showed improvement in the Fugl-Meyer score (average increase 2.5 + 2.1 SD. Individual analyses identified small increases in gray matter volume near the hand knob area of the primary cortex in three of the five patients. Group analyses identified an increase in cortical thickness near the hand knob area of the primary motor cortex, in addition to other sensorimotor regions. CONCLUSION: This small pilot study demonstrates that potentially rehabilitation-associated cortical changes can be identified with MRI in hemispherectomy patients.

Corrigendum to: Glutathione Increase and Seizure Burden Decrease in Patients with Intractable Epilepsy on Ketogenic Diet.

[This corrects the article DOI: 10.14581/jer.23001.].

Regional Cerebral Small Vessel Disease (rCSVD) Score: A clinical MRI grading system validated in a stroke cohort.

BACKGROUND: Current methods for quantitative assessment of cerebral small vessel disease (CSVD) ignore critical aspects of the disease, namely lesion type and regionality. We developed and tested a new scoring system for CSVD, "regional Cerebral Small Vessel Disease" (rCSVD) based on regional assessment of magnetic resonance imaging (MRI) features. METHODS: 141 patients were retrospectively included with a derivation cohort of 46 consecutive brain MRI exams and a validation cohort of 95 patients with known cerebrovascular disease. We compared the predictive value of rCSVD against existing scoring methods. We determined the predictive value of rCSVD score for all-cause mortality and recurrent strokes. RESULTS: 46 (44 male) veteran patients (age: 66-93 years), were included for derivation of the rCSVD score. A non-overlapping validation cohort consisted of 95 patients (89 male; age: 34-91 years) with known cerebrovascular disease were enrolled. Based on ROC analysis with comparison of AUC (Area Under the Curve), "rCSVD" score performed better compared to "total SVD score" and Fazekas score for predicting all-cause mortality (0.75 vs 0.68 vs 0.69; p = 0.046). "rCSVD" and total SVD scores were predictive of recurrent strokes in our validation cohort (p-values 0.004 and 0.001). At a median of 5.1 years (range 2-17 years) follow-up, Kaplan-Meier survival analysis demonstrated an rCSVD score of 2 to be a significant predictor of all-cause-mortality. CONCLUSION: "rCSVD" score can be derived from routine brain MRI, has value in risk stratification of patients at risk of CSVD, and has potential in clinical trials once fully validated in a larger patient cohort.

MR angiographic findings of aberrant right subclavian artery with agenesis of the left common carotid artery and anomalous origin of the vertebral arteries.

INTRODUCTION: Congenital aortic arch anomalies and variants have been extensively characterized in the medical literature. Proper identification of these anomalies is important when surgical or percutaneous interventions are indicated. CASE PRESENTATION: We present a case of a 48-year old male who presented to the emergency department with altered mental status. Magnetic resonance angiography (MRA) findings revealed an aberrant right subclavian artery (ARSA), early bifurcation of the right common carotid artery (CCA) with anomalous origin of the right vertebral artery (VA) from the right common carotid artery bifurcation, anomalous left vertebral artery originating from the aortic arch, and absent left common carotid artery with independent origins of the left external carotid artery (ECA) and internal carotid artery (ICA). No other abnormalities were identified, and the patient demonstrated no symptoms attributable to his vascular anomalies. CONCLUSION: To our knowledge, this unique combination of anomalies has never been reported in the literature. With an understanding of embryological pathways, even exceedingly rare anomalies like this one can be explained.

A structural connectivity atlas of limbic brainstem nuclei.

Background: Understanding the structural connectivity of key brainstem nuclei with limbic cortical regions is essential to the development of therapeutic neuromodulation for depression, chronic pain, addiction, anxiety and movement disorders. Several brainstem nuclei have been identified as the primary central nervous system (CNS) source of important monoaminergic ascending fibers including the noradrenergic locus coeruleus, serotonergic dorsal raphe nucleus, and dopaminergic ventral tegmental area. However, due to practical challenges to their study, there is limited data regarding their in vivo anatomic connectivity in humans. Objective: To evaluate the structural connectivity of the following brainstem nuclei with limbic cortical areas: locus coeruleus, ventral tegmental area, periaqueductal grey, dorsal raphe nucleus, and nucleus tractus solitarius. Additionally, to develop a group average atlas of these limbic brainstem structures to facilitate future analyses. Methods: Each nucleus was manually masked from 197 Human Connectome Project (HCP) structural MRI images using FSL software. Probabilistic tractography was performed using FSL's FMRIB Diffusion Toolbox. Connectivity with limbic cortical regions was calculated and compared between brainstem nuclei. Results were aggregated to produce a freely available MNI structural atlas of limbic brainstem structures. Results: A general trend was observed for a high probability of connectivity to the amygdala, hippocampus and DLPFC with relatively lower connectivity to the orbitofrontal cortex, NAc, hippocampus and insula. The locus coeruleus and nucleus tractus solitarius demonstrated significantly greater connectivity to the DLPFC than amygdala while the periaqueductal grey, dorsal raphe nucleus, and ventral tegmental area did not demonstrate a significant difference between these two structures. Conclusion: Monoaminergic and other modulatory nuclei in the brainstem project widely to cortical limbic regions. We describe the structural connectivity across the several key brainstem nuclei theorized to influence emotion, reward, and cognitive functions. An increased understanding of the anatomic basis of the brainstem's role in emotion and other reward-related processing will support targeted neuromodulatary therapies aimed at alleviating the symptoms of neuropsychiatric disorders.

Pathophysiology, classification, and MRI parallels in microvascular disease of the heart and brain.

Diagnostic imaging technology in vascular disease has long focused on large vessels and the pathologic processes that impact them. With improved diagnostic techniques, investigators are now able to uncover many underlying mechanisms and prognostic factors for microvascular disease. In the heart and brain, these pathologic entities include coronary microvascular disease and cerebral small vessel disease, both of which have significant impact on patients, causing angina, myocardial infarction, heart failure, stroke, and dementia. In the current paper, we will discuss parallels in pathophysiology, classification, and diagnostic modalities, with a focus on the role of magnetic resonance imaging in microvascular disease of the heart and brain. Novel approaches for streamlined imaging of the cardiac and central nervous systems including the use of intravascular contrast agents such as ferumoxytol are presented, and unmet research gaps in diagnostics are summarized.

Magnetic resonance imaging of infectious meningitis and ventriculitis in adults.

Magnetic resonance imaging findings of meningitis are usually nonspecific with respect to the causative pathogen because the brain response to these insults is similar in most cases. In this article, we will use a few representative cases to describe the characteristic magnetic resonance findings of meningitis and its complications, including ventriculitis.

Diffusion restriction in a non-enhancing metastatic brain tumor treated with bevacizumab - recurrent tumor or atypical necrosis?

A 38-year-old female with metastatic brain cancer developed non-enhancing, diffusion restricted lesions following bevacizumab treatment. From our review of the literature, this is the first reported case of this type of lesion. Clinicians should be wary of these lesions, as they can represent either tumor progression or necrosis/effects of chronic hypoxia from anti-angiogenic therapy. Further investigation is necessary to determine the biological mechanism and clinical significance of this type of imaging appearance.

Magnetic resonance imaging appearance and changes on intracavitary Gliadel wafer placement: A pilot study.

AIM: To investigate changes on magnetic resonance imaging (MRI) which occur with intracavitary Gliadel wafer placement in patients with glioblastoma multiforme (GBM). METHODS: This retrospective Health Insurance Portability and Accountability Act-compliant study was approved by the institutional review board, with a waiver of informed consent. A total of eight patients aged 29-67 years with GBM underwent Gliadel wafer placement. T2-weighted/FLAIR images and post-contrast T1-weighted images both before and after wafer placement were retrospectively reviewed in consensus to determine changes in the following parameters: appearance of the pericavitary tissue, pattern of tumor recurrence or progression and appearance of the Gliadel wafer itself. RESULTS: Five out of the eight patients had a progressive increase in enhancement and pericavitary T2/ FLAIR hyperintensity within the first 2 mo and a subsequent decrease in these MRI findings. None of these patients had tumor recurrence within the first 6 mo. Three out of the eight patients demonstrated a progressive increase in enhancement and pericavitary T2 hyperintensity, which continued after the first 6 mo, and were subsequently diagnosed with true tumor progression. There was no increase in distant/nonlocal tumor recurrence. The Gliadel wafer appearance changed over time. CONCLUSION: Pseudoprogression is common after intracavitary Gliadel wafer placement and thus care should be taken before diagnosing tumor progression or recurrence within the first 2 mo.

Evaluation of the coronary sinus on chest computed tomography in patients with and without pulmonary artery hypertension.

OBJECTIVE: To identify and measure the coronary sinus (CS) in patients with and without pulmonary artery hypertension (PAH) using chest computed tomography (CT). METHODS: Using a 4-channel GE LightSpeed CT scanner, nongated axial chest CT images were obtained after intravenous injection of contrast material. Catheterization of the right side of the heart was performed in patients with known or suspected PAH. RESULTS: The CS was identified in all 60 patients (mean +/- SD, 60.5 +/- 17.5 years; 45% men) without PAH (control group) (mean +/- SD, diameter 7.05 +/- 1.90 mm). In 24 patients (9 men; average age +/- SD, 54.1 +/- 14.5 years) with known or suspected PAH (study group), pulmonary artery (PA) pressures were increased; the CS was dilated (mean +/- SD, 9.4 +/- 4. 2 mm); and its size correlated with right atrial pressure (r = 0.358, P = 0.061), mean PA pressure (r = 0.568, P = 0.005), systolic PA pressure (r = 0.375, P = 0.071), and diastolic PA (r = 0.561, P = 0.004). CONCLUSION: The CS is routinely visualized and measurable on chest CT. In patients with PAH, CS dilation is associated with increased PA pressures.

Hippocampal zinc infusion delays the development of afterdischarges and seizures in a kindling model of epilepsy.

PURPOSE: Zinc occurs in high concentration in synaptic vesicles of glutamatergic terminals including hippocampal mossy fibers. This vesicular zinc can be synaptically released during neuronal activity, including seizures. Zinc inhibits certain subtypes of N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA)(A) receptors. By blocking NMDA excitation or GABA inhibition, an excess of zinc may alter the excitability of hippocampal circuits, which contribute to the development of seizures. METHODS: Twenty-one adult Wistar rats were implanted under anesthesia with Alzet pumps releasing vehicle, 10 microM ZnCl(2) or 1,000 microM ZnCl(2), at a rate of 0.25 microl/h continuously into the hippocampal hilus for 4 weeks. Kindling was performed by daily awake commissural stimulation at 60 Hz and afterdischarges were recorded from a dentate gyrus electrode. Development of behavioral Racine seizure stages was recorded by a blinded investigator. RESULTS: The development of behavioral Racine seizure stages was delayed only in rats infused with 1,000 microM ZnCl(2) (p < 0.02). With completion of kindling at stimulation number 20, all groups had reached the same maximum level of behavioral seizures. The expected increased progression of afterdischarge duration was inhibited by both 10 microM ZnCl(2) and 1,000 microM ZnCl(2) infusion compared to control animals (p < 0.01). At stimulation number 18, all groups had reached the same maximum duration of afterdischarges. DISCUSSION: We conclude that excess infused zinc delayed the development of behavioral seizures in a kindling model of epilepsy. These data support the hypothesis that zinc synaptically released during seizures may alter hippocampal excitability similar to zinc infused in our experiment.

MDCT angiography for detection and quantification of small intracranial arteries: comparison with conventional catheter angiography.

OBJECTIVE: MDCT angiography can serve as an alternative to digital subtraction catheter angiography for the study of large and medium-sized arteries. Our goal was to achieve a better understanding of the capabilities and limitations of both MDCT angiography and digital subtraction angiography in the evaluation of intracranial arteries with an average diameter of 1.5 mm or less. MATERIALS AND METHODS: A blinded retrospective analysis of the presence and size of nine small cerebral arteries on both 2D and 3D CT angiography (CTA) was conducted with 27 patients who had normal findings at CTA and digital subtraction angiography. Scans of 455 arterial segments obtained with either 4-MDCT or 16-MDCT were examined by two independent blinded reviewers. The sensitivity and specificity of CTA for each vessel were established. A chi-square test was used to determine interoperator reliability. RESULTS: The smallest arterial size reliably detected with MDCT angiography with our imaging and postprocessing protocol was 0.7 mm versus 0.4 mm for digital subtraction angiography. Interoperator reliability for vessel identification with MDCT angiography was 97% without significant differences in detection rates between 4-MDCT and 16-MDCT. Two-dimensional CTA depicted more than 90% of arteries studied but only 63% of anterior choroidal arteries and 27% of recurrent arteries of Heubner. There were no significant differences in mean arterial sizes measured with 2D CTA versus digital subtraction angiography for six of nine arteries. In six of nine arterial segments with a mean diameter of 1 mm or less, fewer arterial segments were visualized on 3D CTA than on 2D CTA. CONCLUSION: Except for the recurrent artery of Heubner and the anterior choroidal artery, MDCT angiography depicted 90% or more of all examined small intracranial arteries detected with digital subtraction angiography. The mean sensitivity was 0.91, and the mean specificity was 0.7.

Utilization of glutamate/creatine ratios for proton spectroscopic diagnosis of meningiomas.

INTRODUCTION: Our purpose was to determine the potential of metabolites other than alanine to diagnose intracranial meningiomas on proton magnetic resonance spectroscopy (MRS). METHODS: Using a 1.5-T MR system the lesions were initially identified on FLAIR, and T1- and T2-weighted images. Employing standard point-resolved spectroscopy (PRESS) for single voxel proton MRS (TR 1500 ms, TE 30 ms, 128 acquisitions, voxel size 2 x 2 x 2 cm, acquisition time 3.12 min), MR spectra were obtained from 5 patients with meningiomas, from 20 with other intracranial lesions, and from 4 normal controls. Peak heights of nine resonances, including lipid, lactate, alanine, NAA (N-acetylaspartate), beta/gamma-Glx (glutamate + glutamine), creatine, choline, myo-inositol, and alpha-Glx/glutathione, were measured in all spectra. The relative quantity of each metabolite was measured as the ratio of its peak height to the peak height of creatine. RESULTS: Relative quantities of alpha-Glx/glutathione, beta/gamma-Glx, and total Glx/glutathione were significantly elevated in meningiomas compared to the 20 other intracranial lesions and the normal control brains. Alanine was found in four of five meningiomas, but lactate partially masked the alanine in three meningiomas. None of the other lesions or control brains showed an alanine peak. The one meningioma with no alanine and the three others with lactate had elevated Glx. CONCLUSION: While alanine is a relatively unique marker for meningioma, our results support the hypothesis that the combination of glutamate/creatine ratios and alanine on proton MRS is more specific and reliable for the diagnosis of meningiomas than alanine alone.