Guest Lectures

Basic Neurobiology of Seizures

• Seizures are paroxysmal, stereotyped spells caused by abnormal cerebral electrical activity resulting in temporary brain dysfunction
• Hypersynchronous hyperexcitability of neurons characterizes this activity
• Seizures are classified as focal, originating from a specific brain region, or generalized, affecting both hemispheres simultaneously
• An electroencephalogram (EEG) measures electrical activity in the brain and can identify seizures by detecting synchronized neuronal firing patterns

Definition of Epilepsy

• Epilepsy: Defined as two or more unprovoked seizures
• Epilepsy affects approximately 50 million people globally, it is more prevalent in low and middle-income countries
• Common causes include:
  • Idiopathic reasons, accounting for 50-60% of cases with no known cause
  • Brain tumors
  • Stroke
  • Traumatic brain injuries
  • Infections like encephalitis, neurocysticercosis, and malaria
  • Dementia such as Alzheimer's disease
  • Malformations of cortical development
  • Genetic syndromes

Recognizing a Seizure

• Loss of awareness or consciousness
• Involuntary movements like jerking or stiffening
• Unusual sensations include strange smells or visual hallucinations
• Repetitive behaviors such as lip-smacking or hand movements
• Sudden collapse or falls
• Confusion after the event, known as the postictal state
• Different seizure types include focal seizures like temporal, and generalized seizures like absence, myoclonic, tonic, atonic, and tonic-clonic

Seizure Mimics

• Syncope (Fainting):
  • Triggered by posture changes or pain
  • Preceded by lightheadedness, sweating, or graying of vision
  • Rapid recovery
  • Can involve "convulsive syncope"
• Migraine:
  • May involve visual or olfactory hallucinations
  • Associated with headaches and poor concentration
  • Lasts longer than seizures, from minutes to hours
• Panic Attacks:
  • Sudden intense fear with hyperexcitable neuronal circuits
  • Crying is rare
  • Has clear emotional triggers
  • Slower progression
• Other mimics:
  • Transient Ischemic Attacks (TIAs)
  • Transient Global Amnesia
  • Sleep-related disorders (parasomnias)
  • Movement disorders (e.g., tics)
  • Psychogenic Nonepileptic Seizures (PNES)

Seizure First Aid

• Stay calm
• Ensure a safe environment by removing dangerous objects
• Note the time the seizure starts
• Stay with the person, and cushion their head
• Never hold them down or put anything in their mouth
• Call 911 if the seizure lasts more than 5 minutes
• After the seizure ends, place them on their side, check their airway, and assess breathing
• Stay with them until they fully recover

Seizure Safety Tips

• Avoid driving or operating heavy machinery
• Do not swim alone
• Avoid high places (heights, climbing)
• Be cautious around open flames
• Use a buddy system for activities like hiking and biking
• Avoid excessive alcohol and stimulants
• Ensure adequate sleep

Role of GABA and Orexin in Sleep/Wake Regulation

• GABA (γ-Aminobutyric Acid): Acts as an inhibitory neurotransmitter and promotes sleep by suppressing wake-promoting regions
• It contributes to descending (+sleep) pressure in the brain
• Orexin (Hypocretin): A neuropeptide that promotes wakefulness by exciting wake-promoting regions, contributing to ascending (+wake) pressure
• Neural Centers:
  • GABA is released from the ventrolateral preoptic nucleus (VLPO) in the hypothalamus
  • Orexin is produced in the lateral hypothalamus
  • These two systems function in opposition, regulating sleep-wake cycles by balancing inhibitory and excitatory signaling

Clockwork of Mammalian Circadian Rhythms

• Two Forms of Intracellular Feedback Loops:
  • Transcription-Translation Feedback Loops (TTFLs):
    • Found in eukaryotic cells, and regulate gene expression in a rhythmic manner
  • Phosphorylation Feedback Loops:
    • Present in red blood cells and prokaryotes that lack transcriptional mechanisms
• Oscillator Cells: Found throughout the body in tissues such as the lungs, liver, pancreas, kidneys, skin, and various brain regions
• Brain Center for Circadian Rhythms:
  • Suprachiasmatic Nucleus (SCN) in the hypothalamus is the master clock
  • Synchronizes peripheral oscillators via hormonal and neuronal signals.

Cause and Results of Internal Desynchrony

• Cause: Internal desynchrony arises from misalignment between the central clock (SCN) and peripheral clocks in various tissues
• Environmental Induction:
  • Artificial light exposure at night
  • Shift work
  • Jet lag
  • Irregular sleep schedules
• Functional Network-Level Explanation: Desynchronization of signals between SCN and peripheral clocks leads to disrupted hormonal rhythms, metabolism, immune function, and cognitive processes
• Effects:
  • Short-term: Fatigue, cognitive impairment, and mood disturbances
  • Long-term: Increased risk of obesity, diabetes, cardiovascular diseases, and mood disorders

Tissue-Specific Oscillations in Drug Targeting

• Chronotherapy: The timing of drug administration can enhance efficacy and reduce toxicity based on circadian fluctuations in receptor expression
• Examples:
  • Cancer treatment: Chronotherapy improves drug efficacy while reducing side effects like neutropenia and hand-foot syndrome
  • Rheumatoid arthritis: Glucocorticoid therapy is more effective when timed to align with natural inflammatory cycles
• Failure to Account for Rhythms:
  • Increased toxicity: Continuous drug infusion leads to more side effects compared to timed administration
  • Reduced efficacy: If receptors are not optimally expressed, drugs may be less effective

Theoretical Drivers for Sleep

• Homeostatic Drive:
  • Sleep pressure accumulates with wakefulness and is dissipated by sleep
  • Linked to slow-wave activity (SWA) during deep sleep (N3)
• Circadian Drive:
  • Driven by SCN rhythms, influencing when sleep occurs
  • Regulates REM sleep and wakefulness
• Key Differences:
  • Homeostatic drive ensures longer and deeper sleep after deprivation
  • Circadian drive determines when sleep occurs, independent of prior wake duration
• Regulation of Sleep Architecture:
  • Early sleep cycles: More deep sleep (N3) due to homeostatic drive
  • Later cycles: More REM sleep, governed by circadian rhythms

Effects of Sleep Deprivation

• Brain-Specific Effects:
  • Impaired cognitive function: Reduced attention, memory, and decision-making
  • Increased micro-sleeps: Individual cortical areas fall asleep, impairing function
  • Elevated sympathetic tone: Increased stress response
• Broad Systemic Effects:
  • Metabolic dysfunction: Increased risk of obesity and insulin resistance
  • Cardiovascular issues: Higher risk of hypertension and stroke
  • Immune suppression: Increased inflammation and infection risk

Categorization of Biological Functions

• Why Use Categories?
  • Practicality: Simplifies complex biological processes for clinical and research purposes
  • Communication: Enables clear discussion across disciplines
  • Diagnosis and Treatment: Provides structured medical approaches
• Drawbacks:
  • Oversimplification: Ignores gradual transitions and inter-individual differences
  • Arbitrary divisions: May lead to misclassification and inadequate treatment strategies
• Example from Sleep:
  • Sleep is divided into NREM and REM stages, but sleep is a continuous and dynamic process