The “needle free” Brain Stress Test, analogous to the cardiac stress test, was developed in Dr. Mikulis’ lab based on technology that enables rapid, precise, & highly reproducible control of cerebral vasomotor tone yielding MRI maps of 2 biomarkers of vascular performance - speed...

...& magnitude of vascular responses. Comparison of a single individual’s speed and magnitude maps against those of analogous control database maps provides quantitative information on the location and degree of impaired vessel function compared to healthy controls.

This has led to a superior method for assessing, not just the presence, but the efficacy of collateral circulations in patients with steno-occlusive diseases (SOD) within large supply arteries.

Investigation of healthy asymptomatic middle-aged individuals who possess multiple vascular risk factors is currently under development to assess precursors of vascular and Alzheimer’s dementias.

Monogenic forms of Alzheimer's disease (AD) are rare but have taught us important details on pathogenic mechanisms. Specifically, APP (amyloid protein precursor) mutations cause early onset AD by affecting central steps in the amyloid cascade.

The Uppsala APP mutation results in increased beta-secretase cleavage, decreased/shifted alpha-secretase activity, and increased formation of unique amyloid-beta fibril polymorphs.

However, apolipoprotein E (APOE) remains the most powerful genetic risk factor for sporadic AD. Other strongly associated AD risk genes include: BIN1, CLU, ABCA7, CR1, PICALM, & TREM2.

The classic triad for Susac syndrome is: CNS (encephalopathy), eye (visual disturbance), and ear (sensorineural hearing loss) involvement. However, not all individuals with present with the complete triad. https://pubmed.ncbi.nlm.nih.gov/23628737/

MR imaging abnormalities can include "snowball" and "spoke" callosal T2 hyperintense lesions, leptomeningeal enhancement, and diffusion-restricting "string-of-pearls" in the internal capsule https://pubmed.ncbi.nlm.nih.gov/20855088/

Spinal dural arteriovenous (AV) fistulas are a rare, but likely under-diagnosed cause of spinal cord injury and progressive paraplegia. They occur when an abnormal connection arises between the radiculomeningeal artery and radicular veins at a particular spinal level.

The definitive diagnosis of a spinal dural AV fistulas (dAVFs) is made by digital subtraction angiography showing an abnormal arterio-venous connection with dilation of the perimedullary veins.

Microsurgical disconnection is a safe and effective treatment for dAVFs, making it the treatment of choice.

It takes (on average) 15 years and $800M to develop a new drug. And while pharma companies find success in the drug discovery process for many diseases, neurologic drugs are different. The failure rate is very high for neurologic drugs (> 90%).

A lot of the drugs we like to develop for neurologic conditions have parts of the molecule that make them highly susceptible to being destroyed by the liver in the first pass (called the first-pass effect).

Many drugs also do not cross the blood-brain barrier (BBB). Dr. Weaver's lab recently developed a new algorithm to predict whether a molecule will cross the BBB. https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01220

Many human neurological conditions cannot be adequately studied in animal models, leading to the innovative use of human cerebral organoids to study pathophysiology and treatments of intractable epilepsy and other disorders.

Human cerebral organoids are derived from human stem cells (either embryonic or induced pluripotent) from blood or skin sample. The growth media can promote the development and maturation of the cells into specific brain regions.

Patient-specific tissue models can provide pre-clinical trial drug testing in human brain tissue to evaluate therapeutic efficacy and toxicity. This can de-risk the drug development process and potentially save costs along the way.

There is evidence that CT scans with contrast cause 30% more double-stranded breaks in DNA than CT without contrast. See the paper here: https://pubs.rsna.org/doi/10.1148/radiol.2533090468

In a study of 82,861 patients, it was found that for every 10 mSv of low-dose ionizing radiation, there was a 3% increase in the risk of age- and sex-adjusted cancer over a mean follow-up period of 5 years. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3050947/

Concerns about low dose ionizing radiation include cancer risks, cardiovascular risks, and chronic inflammation from an increase of reactive oxygen species. Some interventional radiologists will get a lifetime dose of 1 Gray, many to the left side of the body.

CDKL5 Deficiency Disorder (CDD) is a rare genetic neurodevelopmental disorder that affects mostly girls. It is caused by mutations of X-linked CDKL5 gene. Most cases occur spontaneously with only rare cases of transgenerational inheritance.

Seizures are typically the major comorbidity of CDD and are difficult to manage. Other symptoms include altered sleep cycles, altered autonomic functions such as thermoregulation, low muscle tone, developmental delay, limited speech, and limited hand use.

Dr. Eubanks' lab used CRISPR/Cas 9 editing to introduce the specific Exon 19 del-CT mutation of CDKL5 gene in a mouse line. These personalized mouse models generated an extreme CDKL5 hypomorph, which explains how the mutation causes CDD.

The first big epidemic of encephalitis raged around the time of the First World War and it was worldwide. Although epidemic encephalitis was nothing really new, this epidemic was special because of post-acute parkinsonism and pediatric symptoms.

The diagnosis of encephalitis lethargica (EL) was frequently difficult. Many patients were diagnosed as "hysterical," a disease that does not exist. On the other hand, the diagnosis of "catatonia," a very real disorder, was rarely made.

EL is frequently commingled with the pandemic of "Spanish Flu" that occurred around the same time and it led to the controversial question of coincidence or cause. Modern experiments conducted on archival brain samples failed to confirm a direct relationship between flu and EL.

Even though the same stimulus can be administered, people experience and report pain differently. There are different state and trait attributes that can influence pain mechanisms.

Different behavioural phenotypes related to pain include the A/P dichotomy and high vs low IAP (Intrinsic Attention to Pain).

Regarding sex differences in pain, it was found that when a tonic stimulus is delivered, women had a lower threshold for pain but had greater pain adaptation to sustained stimuli. https://journals.lww.com/pain/Citation/2014/01000/Deconstructing_sex_differences_in_pain_sensitivity.6.aspx

Spontaneous Intracranial Hypotension (SIH) is a syndrome of orthostatic headache due to low CSF pressure. It is most commonly due to CSF leakage from the spinal thecal sac, rather than due to skull base leaks.

It is recommended that dedicated imaging for SIH involves both MR of the head and MR of the entire spine, to look for spinal longitudinal epidural collections (SLECs). These are collections of CSF which have leaked from the spinal canal.

In patients with SIH, the next investigation step we recommend is a digital subtraction myelogram (DSM). This involves injecting x-ray contrast into the spinal canal, and taking x-rays while it runs up along the inside of the spinal canal, looking for leaks.

Patients who have SLECs on MRI are better positioned prone for DSM while those who are SLEC Negative are better positioned lateral for DSM. Read more about the TWH approach here: http://www.ajnr.org/content/40/4/745

A minimally invasive treatment approach is transvenous embolization of CSF leaks (specifically of CSF-venous fistula). This is a new and emerging technique which involves closing off the fistula from inside the blood vessels.

Other treatment approaches include targeted blood patch injection and microsurgery.

Brainstem cavernomas are "slow flow venous malformations" and are associated with a high rate of symptomatic hemorrhages. The predominant intervention for cavernomas is surgical.

Surgical resection should be considered in the setting of multiple hemorrhages in a structurally accessible lesion.

If patients are selected appropriately, the majority achieve surgical cure with either stability or improvement in pre-operative symptoms at 2 years.

Stiff Person Syndrome (SPS) clinical features include: rigidity and stiffness, superimposed spasms, and psychological features, such as generalized anxiety, phobias, and depression.

About 60-80% of SPS cases have autoantibodies against GAD, the enzyme responsible for synthesizing the inhibitory neurotransmitter GABA.

There are two GAD isoforms, GAD65 and GAD67, but it is GAD65 that is the main target for GAD autoantibodies in SPS.

Pathology of Parkinson's disease involves alpha-synuclein-mediated neurodegeneration and transmission through permissive templating, starting with protein misfolding, forming fibrils, and later developing into Lewy bodies.

However, other cellular processes independent of or secondary to alpha-SYN can occur in PD pathogenesis such as impairment of cellular clearance systems, alterations in mitochondrial homeostasis, and inflammation. This shows the complex network of factors involved.

A large portion of PD treatment now focuses on symptomatic management, which involves restoring dopamine levels to normal. Although symptoms (bradykinesia, rest-tremor etc) are often managed effectively, the underlying pathogenic process is not.

See the newest AAN publication for "Dopaminergic Therapy for Motor Symptoms in Early PD Practice Guideline Summary": https://n.neurology.org/content/97/20/942

Dr. Sposato's talk on "Atrial Fibrillation Detected After Stroke (AFDAS): A Clinical Entity Challenging Current Views" explored AFDAS as a distinct clinical entity.

AFDAS is commonly detected after stroke or TIA occurrence and can be either paroxysmal or permanent. AFDAS can also be prevalent (existed before the event) or incident (truly new-onset).

Strokes can induce AF through neurogenic mechanisms. (https://pubmed.ncbi.nlm.nih.gov/32860505/)

Symptomatic therapy for Spinocerebellar Ataxias (SCA) and idiopathic ataxias in general is limited to off-label use of drugs based on anecdotal reports.

Autosomal dominant ataxias are a heterogenous group of disorders with onset typically after the second decade. Diverse features include retinopathy, extra pyramidal or pyramidal signs, peripheral neuropathy, cognitive impairment, and epilepsy.

Genetic treatment techniques available for SCAs include use of iRNA, antisense oligonucleotide-based approaches, and CRISPR. They are promising, powerful, and potentially effective but also biologically and ethically dangerous.

Dr. Radovanovic's talk was on "Brain AVM's: Genetics, Developmental Biology and Perspectives for Targeted Therapies".

Brain AVMs arise from dysregulated angiogenesis, which have genetic influences.

Human brain AVMs are likely caused by germline or somatic mutations in specific genes disrupting the signalling network involved in arteriovenous specification and maintenance.

Activating mutations in the KRAS proto-oncogene (G12V and G12D) were found in the AVMs of 45/72 patients (~63%).

Parkinson's Disease (PD) is one of the fastest growing neurological disorders in prevalence, disability, and death. To date, no disease-modifying therapies, or drugs able to slow disease progression, exist.

Terazosin and other phosphoglycerate kinase 1 activators (PGK1as) stimulate glycolysis and increase cellular ATP levels.

Increased use of PGK1as and tamsulosin are associated with a small decreased risk of PD but whether these improve PD progression is unknown.

Check out her paper published at @MDJ_Journal: https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.28712

Dural arteriovenous fistula (DAVF) can present as headache, dementia, seizure, focal deficits, and tinnitus.

Majority of DAVF cases is idiopathic, with no clear cause. Minority of cases is due to triggers for growth factors and angiogenesis such as trauma, surgery, infection, and sinus thrombosis.

Imaging for DAVF is "chameleon", with presentations of AVM, tumor, CAA, CVT, DVST, venous infarction, and lobar hemorrhage.

ALS: Flail arm variant has a high male-to-female ratio of 10:1. The flail arm variant has median survival of 66 mo and a 5-year survival rate of 53%.

Non-invasive ventilation is the single most efficacious treatment for morbidity and mortality in ALS, with approximately 1 year survival benefit.

Riluzole and edavarone can also be used to manage ALS.

2HELPS2B is a new medical calculator to help guide need for ICU EEG monitoring https://reference.medscape.com/calculator/700/2helps2b-score

New ACNS EEG Terminology for ICU have been recently published April 2021 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135051/pdf/nihms-1696422.pdf

Future considerations of EEG may incorporate artificial intelligence, rapid EEG technology and novel techniques such as Stanford’s brain stethoscope https://www.youtube.com/watch?v=pnGzVW_7cfM

The "Neurobyte" series is the latest initiative by the @KBI_UHN Education committee, aiming to deliver bite-sized information on the field's newest developments to the Twitter community. Follow the @KBI_UHN Twitter page for the live tweets!

Dr. David Mikulis, Director of the Functional Neuroimaging Research Lab at @KBI_UHN, spoke at KBI Neurosciences Rounds on April 21 about the "Brain Stress Test". He shared these important neurobytes:

Dr. Martin Ingelsson, Senior Scientist & Clinician at @KBI_UHN, spoke at KBI Neurosciences Rounds on April 7 about "Identification of Disease-Causing Mutations Shed New Light on the Pathogenesis of #Alzheimers Disease". He shared these important neurobytes:

Dr. Sarah Vinette, PGY3 neurology resident at @uoftmedicine , spoke at @KBI_UHN Neurosciences Rounds on Mar 31: "Headache & Confusion in a 48-year-old Healthy Man" and shared some important neurobytes:

Dr. Chris Lozano, PGY1 neurosurgery resident at @uoftmedicine , spoke at @KBI_UHN Neurosciences Rounds on Mar 31: "A Middle-aged Man with Progressive Paraplegia & Urinary Incontinence" and shared some important neurobytes:

@DrDonWeaver, Director of the Krembil Research Institute at @KBI_UHN, spoke at KBI Neurosciences Rounds on Feb 24 about "Future Neurologic Drugs: Where Will They Come From?". He shared these important neurobytes:

Dr. Peter Carlen, Senior Scientist at @KBI_UHN, spoke at KBI Neurosciences Rounds on Feb 17 about "Your Brain in a Dish: A New Tool for Epilepsy & Other Neurological Disorders". He shared these important neurobytes:

Dr. Kieran Murphy, Vice Chair & Deputy Chief of the Department of Medical Imaging at @KBI_UHN, spoke at KBI Neurosciences Rounds on Feb 10 about "The Role of Antioxidants in Preventing DNA Damage from X-ray Exposure". He shared these important neurobytes:

Dr. James Eubanks, Division Head of Experimental and Translational Neuroscience at @KBI_UHN, spoke at KBI Neurosciences Rounds on Jan 27 about "Personalized Mouse Models for CDKL5 Deficiency Disorder". He shared these important neurobytes:

@DrEdwardShorter, Professor in the History of Medicine at @UofT, spoke at KBI Neurosciences Rounds on Jan 20 about "The Epidemic of Encephalitis Lethargica, 1917-27". He shared these important neurobytes:

Dr. Karen Davis, President of the @CanadianPain Society and division head at @KBI_UHN, spoke at KBI Neurosciences Rounds on Jan 13 about "Brain Imaging & Pain". She shared these important neurobytes:

Dr. Richard Farb, the Site Director of Medical Imaging @SinaiHealth , and Dr. @paddynicholson spoke at @KBI_UHN Neurosciences Rounds on Dec 16th about Spontaneous Intracranial Hypotension & Transvenous Embolization, as treatment. They shared these important neurobytes:

Dr. Alex Landry, PGY2 neurosurgery resident at @uoftmedicine , spoke at @KBI_UHN Neurosciences Rounds on Dec 9: "Brainstem Cavernomas: A Case Discussion & Overview of Treatment Challenges" and shared some important neurobytes:

Dr. Foad Taghdiri ( @FTaghdiri ), PGY3 @UofTNeurology , spoke at @KBI_UHN Neurosciences Rounds on Dec 9th on "Muscle Spasms in a Young Woman" and shared some important neurobytes:

Dr. Anthony Lang, the Chair of Parkinson's Research & the Chair in #MovementDisorders @UHN , spoke at @KBI_UHN Neurosciences Rounds on Dec 2: "Parkinson's Disease: An Update & Overview" and shared some important neurobytes:

Recently, @KBI_UHN and @LHSCCanada had their first-ever joint grand rounds (SYNC) to explore the important neurosciences perspective on the #brain #heart relationship. Dr. @SposatoL , Head of the Stroke Program at @WesternU , shared these neurobytes:

Dr. Renato Munhoz, Co-Director of the Surgical Program & Ataxia Clinic at the Movement Disorders Clinic @UHN , spoke at KBI Neurosciences Rounds on Nov 25: "Gene Therapy for Polyglutamine Spinocerebellar Ataxias" and shared some important neurobytes:

Dr. Ivan Radovanovic presented at this week's @KBI_UHN and @LHSCCanada joint grand rounds (SYNC) on Nov 23rd. Dr. Radovanovic is the Baxter and Alma Ricard Chair of Neurosurgery @uoftmedicine . He shared these neurobytes on Brain Arteriovenous Malformations (AVM's):

Dr. @PritiGros, a Movement Disorders fellow @UHN and a MSc student @ihpmeuoft, spoke at KBI Neuroscience Rounds on Nov 18th, 2021: "Exposure to Phosphoglycerate Kinase 1 Activators and Incidence of Parkinson's Disease," and shared some important neurobytes:

Dr. Everardus Hendriks, a fellow in Interventional Neuroradiology at Toronto Western Hospital, also spoke at KBI Neuroscience Rounds on Nov 11th, 2021: "Dural Arteriovenous Fistula: Architecture & Endovascular Treatment Strategy," and shared some important neurobytes:

Dr. James Im, PGY-3 @UofTNeurology, spoke at KBI Neuroscience Rounds on Nov 11, 2021: "Failed Transmutations," and shared some important neurobytes:

Dr. Suzette LaRoche – President of the American Clinical Neurophysiology Society (ACNS) spoke at KBI Neuroscience Rounds on Nov 4th, 2021: “ ICU EEG Monitoring: History, Recent Advances, & Future Directions” and shared some important neurobytes: