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Challenges and Opportunities in Brain Imaging

Challenges and Opportunities in Brain Imaging

Bremner, J., Piccinelli, M., Garcia, E., Moncayo, V., Elon, L., Nye, J. A., David, C., Washington, B., Ortega, R., Desai, S., Okoh, A. K., Cheung, B., Soyebo, B., Shallenberger, L., Raggi, P., Shah, A., Daaboul, O., Jajeh, M., Ziegler, C., . . . Vaccarino, V. (2023)


Objective: Coronary heart disease is a leading cause of death and disability. Although psychological stress has been identified as an important potential contributor, mechanisms by which stress increases risk of heart disease and mortality are not fully understood. The purpose of this study was to assess mechanisms by which stress acts through the brain and heart to confer increased CHD risk.

Methods: Coronary Heart Disease patients (N=10) underwent cardiac imaging with [Tc-99m] sestamibi single photon emission tomography at rest and during a public speaking mental stress task. Patients returned for a second day and underwent positron emission tomography imaging of the brain, heart, bone marrow, aorta (indicating inflammation) and subcutaneous adipose tissue, after injection of [18F]2-fluoro-2-deoxyglucose for assessment of glucose uptake followed mental stress. Patients with (N=4) and without (N=6) mental stress-induced myocardial ischemia were compared for glucose uptake in brain, heart, adipose tissue and aorta with mental stress.

Results: Patients with mental stress-induced ischemia showed a pattern of increased uptake in the heart, medial prefrontal cortex, and adipose tissue with stress. In the heart disease group as a whole, activity increase with stress in the medial prefrontal brain and amygdala correlated with stress-induced increases in spleen (r=0.69, p=0.038; and r=0.69, p=0.04 respectfully). Stress-induced frontal lobe increased uptake correlated with stress-induced aorta uptake (r=0.71, p=0.016). Activity in insula and medial prefrontal cortex was correlated with post-stress activity in bone marrow and adipose tissue. Activity in other brain areas not implicated in stress did not show similar correlations. Increases in medial prefrontal activity with stress correlated with increased cardiac glucose uptake with stress, suggestive of myocardial ischemia (r=0.85, p=0.004). Conclusions: These findings suggest a link between brain response to stress in key areas mediating emotion and peripheral organs involved in inflammation and hematopoietic activity, as well as myocardial ischemia, in Coronary Heart Disease patients.

Hadanny, A., Maroon, J. C., & Efrati, S. (2023)


IntroductionThe application of hyperbaric oxygen therapy for patients with both acute and chronic traumatic brain injury has been suggested for over five decades. In the past decade, the design and quality of studies were more detailed and thorough leading to an improved unerstanding of the uses of HBOT and the profiles of the patients who can benefit the most.

ObjectivesPerform a comprehensive literature review of hyperbaric oxygen therapy application for the treatment of patients with both acute, subacute and chronic traumatic brain injury.

MethodsExtensive literature search from 1969 to April 2023 was performed on April 1st 2023 within the following databases: Cochrane Library, PubMed, Google Scholar, and Web of Science, including humans clinical data, in articles providing information on the type of treatment and clinical outcomes. Articles were first categorized into acute-subacute traumatic brain inury and chronic traumatic brain injury and further classified into low, medium or high level quality.

ResultsThere was high level evidence including nine randomized controlled trials, one meta-analysis and two prospective study evaluating the clinical effects of hyperbaric oxygen therapy in patients suffering from traumatic brain injuries in the acute and subacute settings. Mortality was significantly reduced in all studies that used it as an endpoint, while favorable functional outcomes in survivors showed mixed results.

In chronic severe traumatic brain injury, there is low to moderate evidence including two uncontrolled prospective studies, two cohort studies and eight case reports suggesting improved outcomes.

In chronic mild traumatic brain injury, there is high level evidence including seven randomized controlled trials, and six prospective studies suggesting significant improvement in cognitive function, symptoms and quality of life.

Conclusions: Hyperbaric oxygen therapy may be recommended in acute moderate-severe traumatic brain injury patients (Type 2a recommendation, level A evidence). However, further studies are needed to both evaluate outcomes and to determine the optimal treatment protocols for the different types of injuries (Type 1 recommendation, level A evidence).

Hyperbaric oxygen threrapy should be recommended in chronic traumatic brain injury for a selected group of patients suffering from prolonged post-concussion syndrome who have clear evidence of metabolic dysfunctional brain regions as determined by neuroimaging (Type 2a recommendation, level B-R evidence). Patients should be properly evaluated by standardized cognitive tests and functional brain imaging (Type 1 recommendation, level B-R evidence).

Yang, F., Bowden, G., Patel, S., Ghosh, S., Yun, J., Aronyk, K., Amanie, J., Warkentin, B., Larocque, M., Heikal, A., Rowe, L., Wheatley, B., & Fairchild, A. (2022)


Background. Frameless fixation with a thermoplastic mask is an alternative to traditional frame-based immobilization for Gamma-Knife stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT). However, interruptions during beam-on time can significantly prolong treatment delivery, impacting patient experience and unit workflow.

Aim. We investigated clinical and technical predictors of treatment interruptions, and the phases of treatment during which interruptions are most likely to occur.

Methods. Patients undergoing frameless Gamma Knife SRS or FSRT in 2020 were retrospectively reviewed. Clinical parameters were extracted from electronic medical records. Dosimetric and treatment interruption data were obtained from Gamma Knife treatment reports. Univariate and multivariate analyses analyzed technical and clinical predictors of treatment interruptions.

Results. Our cohort included 84 patients receiving 141 fractions encompassing 255 lesions. 49/84 (58.3%) were female, 79/84 (94.0%) had brain metastases, 49/84 (58.3%) were taking dexamethasone and 30/84 (35.7%) used analgesics. 89/106 (84.0%) courses were single fractions. Mean planned beam-on time was 37.1 minutes (range 7.1-118.8 min) versus a total bed time of 64.9 minutes (range 15-252min) per fraction. 64.5% (91/141) of fractions were interrupted at least once; 12/141 fractions were paused 20 times or more, with a maximum 54 pauses. The mean number of pauses per quartile decreased the further the patient proceeded in beam-on time, and patients receiving first lifetime cranial radiation paused more often than during subsequent fractions. At least one pause occurred in 100% of fractions with a planned beam-on time exceeding 60 minutes. Planned beam-on time, number of gating events and high-definition motion management alarms significantly correlated with total number of pauses on multivariate analysis (all p<0.0001); these three factors, along with prep time and number of operator-initiated pauses, predicted total time on the Gamma Knife couch (all p<0.0001). Clinical factors, medication use, and prior SRS/FSRT were not predictive of pauses.

Conclusions. Planned beam-on time, number of gating events and high-definition motion management alarms significantly predicted likelihood of interruptions during frameless Gamma Knife SRS/FSRT. These factors should be considered in selection of immobilization method, especially if exceeding 60 minutes.

Muñoz, A., Marı́N, P., & Martínez, P. (2022)


Background: Communication or anatomic continuity of the fourth ventricle outlet (FVO) with the central cervical ependymal canal (CCEC) of the spinal cord in both humans and mammals is controversial.

Aim: We hypothesize that in chronic inflammatory brain conditions (CIBC) and in early stages of age this communication can be reopened. For this purpose we have conducted a study to check the potential continuity of FVO with the CCEC of the spinal cord in small domestic carnivores presenting with obstructive hydrocephalus (OH) secondary to CIBC.

Methods: Retrospective neuroradiological evaluation of a case series involving 23 domestic carnivores with CIBC presenting with both OH and cervical hydromyelia/syringomyelia. MR images checked specifically the continuity between the FVO and the CCEC.

Results: There were 18 adult and five young domestic carnivores. Anatomical continuity between the FVO and a dilated CCEC (hydromyelia) could be demonstrated on MR imaging in all young cases but in only 16 % of adult cases.

Conclusions: This study provides additional insights into understanding the relationship between the development of hydrocephalus and hydro/syringomyelia. MRI findings support that domestic carnivores have a virtual CCEC that is connected with the FVO at birth and might disappears over the years in normal, healthy animals, thus explaining hydromyelia in early stages of age rather than syringomyelia, in hydrocephalic conditions. When this anatomical continuity is present, the hydrodynamic theory have a pivotal role in the pathogenesis of hydromyelia. If not (most adult cases) other mechanisms may be activated and lead to spinal cord syringomyelia.

Nada, A., Mahmoud, E., Ahsan, H., Biedermann, G., & Cousins, J. P. (2022)


Purpose: To evaluate the longitudinal change of intra-tumoral susceptibility signal (ITSS) on high-resolution SWI as an adjunctive imaging tool to evaluate treatment response of brain metastasis following stereotactic radiosurgery. This approach will allow further stratification of the patients and guide clinical decision making.

Methods: An IRB approved retrospective study included 63 brain metastatic lesions within 49 patients (33 females and 16 males) who have undergone stereotactic radiosurgery with at least one follow-up MRI and available clinical data. The average age was 63.17 years (±1.48, ranged from 34-83 years). The longitudinal change in ITSS was categorized into 3 groups; increased, stable and decreased. The treatment response of each lesion was evaluated according to the longitudinal change in size, enhancement and susceptibility at the baseline and follow-up MRIs. Chi-square test was used to compare differences in categorical variables. Receiver operating characteristics (ROC) curve was used to evaluate the accuracy of including longitudinal change in ITSS with size and enhancement pattern in determining the treatment response following SRS.

Results: Our results demonstrated higher sensitivity and specificity when including longitudinal change in ITSS with size and enhancement for the evaluation of the treatment response of brain metastatic lesions treated with SRS. There was statistically significant difference between the different ITSS and enhancement patterns at baseline and follow-up MRIs (Wilcoxon Signed Ranks Test (p = .000, and .003) respectively. The multiparametric analysis of the longitudinal change in size, contrast enhancement, and ITSS in the evaluation of treatment response in the follow-up MRIs, showed that the sensitivity and specificity significantly improved (AUC 0.953).

Conclusion: High resolution SWI can contribute as an imaging biomarker with supplemental information for monitoring treatment and predicting treatment response. High resolution SWI can complement the standard contrast enhanced T1 images to evaluate treatment response with a multiparametric MRI approach.

Broderick, P. A. (2022b)


Neuromolecular Imaging (NMI) for white matter detection, distinct from that of gray matter is an inventive art. (1) This imaging technique demonstrates, for the first time, a LIVE and continuous videotracking nanotechnology for distinguishing white matter from gray matter in the brain of epilepsy patients, online, in real time and for long periods of time. NMI is known to perform with unrivaled temporal and spatial operational reliability and reproducibility Thus, a nanotechnology for white matter disorders, for example, leukodystrophies, is published for the first time. The purpose of this paper is to present a critical distinction for white versus gray matter in hippocampal and neocortical resected tissue derived from mesial and neocortical temporal lobe epilepsy patients en bloc during intraoperative surgery; the patients present as medically refractory to classical pharmacotherapeutics. The tiny carbon-based lipid polymeric sensor, the BRODERICK PROBE® readily sees white matter in contrast to gray matter in brain neuroanatomic substrates as it continually senses the glia or the neuron, white or gray matter, respectively, with distinct clarity via electroactive signal processing. The difference between white and gray matter is striking as the videotrace slides smoothly from the white to the gray milieu. Thus, a primary in vivo white matter nanotechnology is presented to advance diagnosis and therapy for white and gray matter abnormalities in the brain and spinal cord.

Shoemaker, R., Heyman, A., & David, L. (2023)


Problems with executive cognitive function, including recent memory, concentration, word finding, confusion, decreased assimilation, and disorientation, can have a variety of sources of disease, including inflammation, metabolic disturbances, and degenerative processes that are typically found in diseases where chronic fatigue is present. The problems presented by multiple coexisting cognitive symptoms are finding: 1) a single diagnostic test that has a history of use by clinicians working with brain-injured patients, such as NeuroQuant (NQ); 2) that is affordable, accurate, and reliable to use as a measure of benefits, or lack of same; and 3) screening, causation, and sequential features of therapy. Furthermore, the complexity of brain injury shows us the limitations of human versus machine-based testing, with advances in transcriptomics leading the way in a new world of diagnostics and therapies that follow gene activation studies.

The objective of this report was to retrospectively look at results of the transcriptomic testing of white blood cells, combined with a brain volumetric imaging study, in an observational study to provide a basis to identify the specific causation of brain injury caused by exposure to the interior environment of water-damaged buildings (WDB). By comparing transcriptomic abnormalities with known volumetric patterns of injury to cortical grey matter, enlargement of superior lateral ventricles and atrophy of grey matter nuclei, we demonstrate the feasibility of treatment of brain injury employing noninvasive methods in preparation for novel treatments previously shown to be effective. We intend to use these tests sequentially in a before-and-after fashion to show correction of metabolic and inflammatory conditions found in chronic inflammatory response syndrome (CIRS) in a subsequent study.

Panagopoulos, D., Strantzalis, G., Gavra, M., Efstathios, B., Korfias, S., & Karydakis, P. (2022)


Chiari malformations comprise a group of disorders, which share in common inherent anatomical abnormalities that involve the region of the brain stem and cerebellum, eventually coexisting with entities such as hydrocephalus, spina bifida, syringomyelia and tethered cord syndrome.In the mean-time, from the original description of this syndrome, several researchers have focused on an effort to elucidate the pathogenesis of Chiari malformation from a point of view that it is a primary neural anomaly.

The aim of the current review is to investigate the time course of our knowledge regarding Chiari malformation, which has expanded significant in the past decades. As new insight has occurred regarding the pathophysiology and natural history of Chiari I malformation (CIM), in association with the widespread availability of MRI,the treatment modalities and algorithm for this patient population has been substantially evolved.Our purpose is to present a review of CIM and its most significant associated comorbidities,comment on techniques for surgical intervention and their expected outcomes.

There is a bulk of literature reviews centered on Chiari malformations· in this context, we attempted a literature review, including a discussion centered onthe historical background, anatomical forms, pathophysiology, clinical presentation, relationships with other diseases and diagnostic procedures for these abnormalities. Moreover, a bibliographic search was performed, using Thomson Reuters web of Science and Pubmed databases, in order to identify the most noteworthy papers about Chiari Syndrome. The following parameters were recorded: article titles, number of total citations and citations per year, authors’ names, authors’ h-index, institution and country where the research took place, year of publication, the journal of publication and journal’s impact factor. In addition, we reviewed the journals’ Impact Factor and SCImago Journal Rank (SJR). To obtain all those parameters, besides Web of sciences, we utilized Scopus, SCimago Journal and Country rankings, and In Cites Journal Citation Reports.

Our search resulted in 9.972 articles, published from 1855 until now (March2022). All articles are in English. The 50 most cited papers are presented in Table S1. All of them combined have been cited 8.999 times, in 3.262 different articles, with an average citation per item of 179.98.

We have attempted to present a thorough overview of this group of disorders, as well as to trace the evolution of our knowledge regarding the anatomical abnormalities associated with this condition, imaging and treatment gold standards and future perspectives.

The real pathophysiology, embryological background and natural history of CM have still not been entirely elucidated. This is in concordance with the fact that new suggestions have been submitted for the management of this malformation and more sophisticated imaging techniques have been introduced, in order to investigate in more details, the diagnosis. However, a lot of controversies remain, mainly centered on the optimum strategy which should be selected for selection of the appropriate surgical candidates and most efficacious treatment protocols, in order to obtain efficient decompression of the cranio-cervical junction.

Ono, H., Nishijima, Y., Satoh, M., Kitamura, S., Naitoh, Y., Suzuki, K., Fujii, N., Kikura, R., & Ohta, S. (2022)


Introduction: Molecular hydrogen (H2) has emerged as a therapeutic medical gas that exerts multiple functions. H2 inhalation has been approved as safe, and some clinical studies showed that it effectively improved conditions of patients with a variety of disorders such as stroke, heart infarction, chronic obstructive pulmonary disease, cancer, and COVID-19. Urinary and fecal incontinences are unavoidable symptoms of advanced Alzheimer’s disease (AD) dementia. In particular, fecal incontinence increases the level of confusion for patients and caretakers suffer from increased workloads.

Materials and Methods: To assess the integrity of the neurons related to AD, the bundles of neurons passing through the hippocampus were visualized by modified diffusion tensor imaging (DTI) technology using advanced magnetic resonance imaging (MRI)

Results: A 79-year-old woman with advanced AD continued to inhale 3% H2 gas containing 21% oxygen twice daily for 1 hour and maintained clinical observations for 2 years. After the long period of inhalation of H2 gas, the patient went to the bathroom by herself for adequate excretion. She remained to be able to go to the bathroom for her bowel movements in time, afterwards. After the long-term inhalation of H2 gas, her MRI of the brain to generate DTI images with an anisotropic (FA) value of 0.2 (FA = 0.2) showed improved integrity of the hippocampal neurons along with these clinical improvements.

Conclusion: This case report casts the question on the current understanding that the advanced and severe AD patients will never improve.

Shoemaker, R., Heyman, A., & Lark, D. (2023)


Beginning with Possible Estuarine Associated Syndrome (PEAS) in 1998 and followed by numerous studies on similar types of exposures, patients with illness associated with biotoxin exposure routinely have had symptom rosters dominated by executive cognitive dysfunction, including recent memory deficits, difficulty in concentration, difficulty with word finding, decreased assimilation of new knowledge, confusion and disorientation, tremors, headaches, vertigo, and unusual pains. In addition, tremors, headaches, vertigo, unusual pains and metallic taste. Toxins involved variously have included those found in toxin-forming dinoflagellates, including Pfiesteria and ciguatera; cyanobacteria, including Microcystis, Cylindrospermopsis and Lyngbya wollei; post Lyme syndrome and Babesia; as well as organisms found in damp buildings, including Aspergillus versicolor and A. penicillioides, Stachybotrys chartarum, Chaetomium globosum, Wallemia sebi, Actinobacteria species, especially Corynebacteria tuberculostearicum and Propionibacterium acnes; as well as bacterial endotoxins and beta-glucans. These illnesses have been called chronic inflammatory response syndromes (CIRS).

The mechanism of neurologic findings has remained elusive despite studies showing successful treatment with intranasal vasoactive intestinal polypeptide (VIP). Neurocognitive testing has only been performed in PEAS patients, showing profound deficits in learning and higher cognitive functioning. These CIRS patients have had brain imaging without consistent findings, including MRI, EEG, and CT of the brain. NeuroQuant has shown findings that fit a “fingerprint” found in patients with specific causation and confirmed exposure to Actinobacteria and endotoxins. Fungal exposure shows disproportionate enlargement due to interstitial edema in the forebrain parenchyma and cortical grey, with a diminished caudate nucleus size. These findings have not been found in controls. The recent inclusion of transcriptomic studies using GENIE has confirmed that specific causation can be identified for Actinobacteria (48% of total confirmed cases), bacterial endotoxins (28%) and fungi (7%) in CIRS patients. The combination of NeuroQuant and GENIE has implicated excessive production of cytoskeletal tubulin genes TUBA4A and TUBB1 as risk factors for specific fingerprints for die-back degenerative central nervous system (CNS) injury in patients with illnesses associated variously with exposure to Actinobacteria, fungi and endotoxins.

This study seeks to implicate a causal abnormality of excessive expression of tubulin genes TUBA4A and TUBB1. Given the role of these genes in die-back CNS degenerative diseases, such as Alzheimer’s, amyotrophic lateral sclerosis and Parkinson’s disease, and anecdotal successful treatment of CIRS patients with elevated TUBA4A and TUBB1, we suggest the possibility of treatment of tubulin excess may have a role in clinical improvement seen in die-back CNS degenerative diseases. Elevated levels of MAPK are also risk factors when combined with elevated levels of TUBA4A and TUBBI.

Lodi, Y., Bowen, A., Soltani, A., Khan, I., Polavarapu, H., & Hourani, A. (2023)


Background: Despite the advancement in acute ischemic stroke with large vessel occlusion (LVO), golden time is lost in assessment lengthy neurological examination and redundantly in the Emergency department, often after emergency medical service prehospital stroke scale evaluation indicating possible LVO. A simple acute ischemic stroke scale (AISS) of the cortical representations of the anterior circulation can rapidly predict LVO, saving precious time to initiate early intravenous tissue plasminogen activator and endovascular mechanical thrombectomy. We proposed an ASIS in the emergency department called Gaze Weakness Neglect Speech (GWNS) to evaluate its feasibility and predictability for the detection of LVO in anterior circulation in the emergency department. Additionally, to evaluate if time can be gained that has been lost in obtaining National Institute of Health stroke Scale (NIHSS) and computed tomographic angiography (CTA), avoiding unnecessary radiation.

Methods: This is a prospective observational study. An institutional review board permission was obtained, and patient enrollment started in January 2020 and ended in January 2021. Consecutive patients from January 2020 to September 2021 were selected from the database. The GWNS stroke scale was used by stroke and vascular neurologist during the emergency triage. The GWNS stroke scale scores range from 0 to 4 (1 for positive 0 for negative). The GWNS stroke scale assesses gaze deviation or gaze preference (G), presence of any weakness (W), neglect/disregard (N), and any speech impairment (S). Demographic data, CTA/cerebral angiographic data, and scores from NIHSS were also collected. The collected data was analyzed by a biostatistician to determine the association between the GWNS scale score and LVO.

Results: In our study,109 qualifying patients were selected. Fifty-eight patients had GWNS stroke scale score of 3 or 4, with 57 having confirmed LVO and 1 presenting after a seizure.  The GWNS stroke score ≥3 (0.86) correlated with LVO better than NIHSS (0.67), regardless of hemisphere side involvement. The GWNS stroke scale score of ≥3 also was effective in detection of proximal and distal blood vessels occlusion in the anterior circulation (Internal carotid artery, middle cerebral artery and its branches).  A GWNS stroke scale score of ≥3 with presence of gaze was the most predictive for LVO (0.9) followed by neglect/disregards (0.8). The time to obtain GWNS stroke scale was 1.5 minutes (range 1-3) and time to obtain/interpretation CTA was 41.3 +/- 7.4 minutes after emergency department arrival (range: 29-51 minutes).

Conclusions: Our Gaze Weakness Neglect Speech stroke scale can be performed rapidly in the emergency department and is highly predictive of LVO in the internal carotid artery, middle cerebral artery and middle cerebral branches. A GWNS stroke scale score of ≥3 is highly predictive of LVO, especially when gaze or neglect is present. Patients can potentially bypass CTA or advanced imaging in future studies, saving precious time and millions of brain cells for better outcome.

Rafya, M., Bou-Ouhrich, Y., Ezahiri, M., Echchafi, R., Ouamer, F., & Чарра, Б. (2023)


Herpetic encephalitis is the most common viral encephalitis in adults and is the most severe form of   herpes simplex virus infection. The diagnosis is based on polymerase chain reaction in cerebrospinal fluid, as well as brain magnetic resonance imaging. Although intra cerebral petechial hemorrhage has been described during herpetic encephalitis, intraparenchymal cerebral hematoma is an extremely rare form.

The absence of response to treatment or the worsening of clinical symptoms should suspect the diagnosis. The medical treatment is based on acyclovir which should be initiated as soon as the diagnosis is suspected. Surgical treatment is based on decompressive craniotomy.

Herein, we report the case of a 62-year-old man in whom the diagnosis of herpetic encephalitis was confirmed, and the patient was put on acyclovir-based medical treatment. The follow-up was marked by the appearance of an intra-parenchymal hematoma for which the patient had a decompressive craniotomy. The evolution was marked by neurological worsening leading to the death of the patient.