Epilepsy, Sleep, NeuroImaging Flashcards
What is Epilepsy?
A disorder of brain synchronization
Seizure type corresponds to network location
Causes of Epilepsy
ACQUIRED: Many Pathologies
Degenerative Infection Neoplastic Vascular Trauma Congenital
Do gene pathways converge onto a common cellular mechanism?
YES, Inhibition is a MAJOR TARGET of Epilepsy Genes
Molecular Pathogenesis of Epilepsy
- Channelopathies
- Proliferation
- Migration
- Cell Death
- Dysregulation of other genes
Epileptogenic Mutations Reduce CNS Synaptic Inhibition (Brake failure)
Epileptogenic Channelopathies
Prolong Membrane Depolarization
Channelopathies’ modify neuronal firing and produce alterations in brain development
ONE single gene defect may produce complex developmental brain lesion!
Differentiation leads to excitability
Cortical Interneuron Migration Failure
Transplanting cortical GABA interneruon reduce seizure
Knockout of UPAR (Urokinase-type plasminogin activator receptor)
Seizures Alter Brain Circuits: Stem Cell Proliferation, Neosynaptogenesis
Dentate Granule Cell Neurogenesis is increased by seizures
Seizures Alter Brain Circuits
Seizures trigger axonal sprouting and new synapses
Granule cells send new axon branches to form aberrant circuits
Summary of Epilepsy
- Synchronization defects cause seizures
- Many different molecular causes
- Single genes lead to epilepsy by disrupting development, wiring, synapses, firing
- Better understanding of epileptic networks is leading to new therapies
Why Sleep?
ENERGY is CONSERVing
Biological “Clocks”
1. Evolved to maintain appropriate sleep/wake cycle despite variable light/dark cycle 3. The “clock” is primarily influenced by light and temperature 
Sensing Light
Photosensitive RGCs contain melanopsin
- Depolarized by light
- Rods and cones can mediate some circadian entrainment
Sensing Light
Pineal Gland
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- Modulated by SCG
- Synthesizes & releases the sleep- promoting hormone melatonin
- Melatonin interacts with receptors in the SCN, influences sleep/wake
Sensing Light
Retinal Ganglion Cell
Projects to the SCN
Sensing Light
Paraventricular Nucleus
Activation of SCN evokes responses in the PVN
Sensing Light
Suprachiasmatic Nucleus
Main site of circadian rhythm control of homeostatic functions
Sensing Light
Superior Cervical Ganglion
Activated by Intermediolateral cell column
Retinal Ganglion Cell
Projects to the SCN
Paraventricular Nucleus
Activation of SCN evokes responses in the PVN
Suprachiasmatic Nucleus
Main site of circadian rhythm control of homeostatic functions
Superior Cervical Ganglion
Activated by Intermediolateral cell column
Intermediolateral Cell Column
Activated by PVN
Sleep Stages
Awake Stage 1 Stage 2 Stage 3 Stage 4 REM Sleep
Physiological Changes in Sleep States
- Body parameters decrease from stage I to IV of sleep
- REM sleep is characterized by increases in blood pressure, heart rate, and metabolism to nearly awake levels
- REM sleep is named for the rapid, ballistic eye movements, pupillary constriction, and paralysis of large muscle groups
- Dreaming typically occurs in REM
Functions of Sleep and Dreaming
- Purposes of various sleep states are not well understood
- non-REM is likely at least partly restorative
- REM sleep is where dreaming occurs
- - REM dreams are more emotional and vivid
- - Deprivation of REM sleep does not have any negative outcomes on the time scales it has been studied - Sleep in general is likely important for learning and memory consolidation
NEURAL CIRCUITS:
REM Sleep paralysis
- Relative paralysis arises from increased activity in GABAergic neurons in the pontine reticular formation
- Through projections, the lower motor neurons in the spinal cord are inhibited
NEURAL CIRCUITS:
Reticular Activating System (RAS)
- Electrical stimulation of the RAS causes a state of arousal and wakefulness
- Located at the junction of the pons and midbrain
NEURAL CIRCUITS:
Thalamus
Electrical stimulation of the Thalamus with low- frequency pulses in an awake cat causes
slow-wave sleep
NEURAL CIRCUITS:
REM Sleep
- During REM sleep, EEG waves originate in the PRF and propogate through the LGN to the occipital cortex. These PGO waves provide a useful marker of the beginning of REM sleep and are another marker of the brainstem activating the cortex.
- Without visual stimuli, the pontine reticular formation endogenously signals the superior colliculus
- Collicular neurons project to the PPRF, which is involved in the saccade
- Increased limbic system activity
- Decreased influence of the frontal cortex
NEURAL CIRCUITS:
Sleep/Wake Cycle
- Cholinergic nuclei are characterized by high discharge rates during wake/REM and low discharge during non-REM sleep
- These nuclei cause “desynchronization” of the EEG when activated
- Lateral hypothalamus activates the Tuberomammillary nucleus of the hypothalamus
- TMN activates both the locus coeruleus and raphe nucleus
- These circuits are responsible for the awake state
- Ventrolateral preoptic nucleus of the hypothalamus can inhibit the TMN
- Activation of the VPLO is responsible for the onset of sleep
- VPLO lesions cause insomnia
NEURAL CIRCUITS
Thalamocortical Interactions
- The sleep/wake effects of the brainstem nuclei are achieved by modulating the interactions between the thalamus and the cortex
- The activity of several ascending systems from the brainstem decreases both the rhythmic bursting and the related synchronized activity of cortical neurons
- Thalamocortical neurons receive projections from brainstem nuclei and project to cortical pyramidal cells
- Thalamocortical neurons have only two stable states: bursting or tonically active
- Bursting occurs when neurons in the thalamus become synchronized with those in the cortex, “disconnecting” the cortex from the outside world
- This is maximal during slow-wave sleep
- The tonically active state is generated when the neurons are depolarized, which happens when the RAS generates wakefulness
- TC neurons transmit information to the cortex related to spike trains encoding peripheral stimuli
NEURAL CIRCUITS
Thalamocortical Interactions and Sleep Studies
- Bursting can be transformed to tonically active by cholinergic or monoaminergic projections
- Bursting is stabilzed by hyperpolarization of thalamic cells
– Hyperpolarization occurs by GABAergic projections from the reticular nucleus- These neurons receive ascending information from reticular cells and descending information from cortex
- Sleep spindles are generated when neurons in the RAS have a burst of activity
- In turn this causes TC cells to generate short bursts of action potentials

Sleep Disorders: INSOMNIA
- Short term insomnia has many causes and can usually be avoided by improving sleep habits, avoiding stimulants, and (sometimes) by taking sleep-promoting medications
- Debilitating insomnia can be associated with major depression and is a problem in the elderly
- Depression and aging likely affect the cholinergic, adrenerigic, and serotinergic systems
Sleep Disorders: APNEA
- Pattern of interrupted breathing during sleep
- A person wakes many times a night and experiences little or no slow-wave sleep and REM sleep
- Continual tiredness and depression are symptoms
- Can even lead to death due to airway restriction
- In normal sleep, breathing slows, muscle tone decreases. If the output of the brainstem circuitry regulating commands to the chest wall or to pharyngeal muscles is decreased enough, or if the airway is compressed due to obesity, the pharynx collapses as muscles relax. Carbon dioxide levels rise, which causes a reflex inhalation, which generally wakes the individual.
- Most widely used remedy is a positive-pressure max that enhances airflow during sleep
Sleep Disorders: RESTLESS LEG SYNDROME
- Unpleasant crawling, prickling, or tingling sensations in one or both legs and feet, and the urge to move them to obtain relief
- - Occurs after sitting or lying down for long periods
- - Constant leg movement during the day and fragmented sleep at night
- - Mild cases can be helped by heat, massaging the legs, or avoiding stimulants
- - Severe cases can be helped by benzodiazepines
Sleep Disorders: NARCOLEPSY
- Frequent “REM attacks” during the day where the individual enters REM sleep directly from wakefulness.
- Attacks can last from 30 seconds to 30 minutes or more
- Affects mostly men; about 250,000 people in the US
- Onset of sleep is abrupt and entails a temporary loss of motor control called cataplexy
- In dogs, narcolepsy is caused by mutations to the orexin-2 receptor gene (found in the TRG)
- Mutations either cause hyperexcitability or impairment of inhibition of the circuits that cause REM sleep
- Treatment is usually with stimulants such as methylphenidate or amphetamines
Sleep Disorders: CHRONIC FATIGUE SYNDROME
- Debilitating fatigue along with unrefreshing sleep, memory and concentration problems, a feeling of extraordinary tiredness following routine exercise
- 6+ months of persistent or relapsing fatigue that impairs normal function
- May also have sore lymph nodes, sore throat, muscle pain, joint pain, and headaches
- Onset is generally after a flu-like illness, with only a minor number of patients returning to a normal level or figor
- Treatment is usually symptom management and improving coping
Summary for SLEEP
- All animals exhibit a restorative cycle of rest
- Only mammals have REM/non-REM cycle
- Why we need suspended consciousness and decreased metabolism is not known
- Our organized sleep progression is generated by brainstem nuclei
- This is achieved through modulation of activity of the thalamocortical loop
- The circadian clock is located in the suprachiasmatic nucleus and VLPO of the hypothalamus and influences these systems
- The “clock” adjusts sleep/wake to the appropriate durations
TAXONOMY of Neuroimaging Methods
- External Ionizing Radiation
- CT, Angiogram/Arteriogram, X-Ray - Internal Ionizing Radiation
- PET, SPECT - Non-Ionizing Radiation (Radio Waves)
- MRI, fMRI, MR Angiography, Diffusion Imaging, MR Spectroscopy - Accessory (non-imaging) Methods
- MEG, EEG
MRI: Magnetic Resonance Imaging
PROS:
incredible images, advancing very rapidly extremely high resolution, extremely versatile, NO ionizing radiation
CONS:
moderately expensive, complex, some contraindications (ferrous metal in the body, cochlear implants ALWAYS, possibly pacemakers, vagal nerve stimulators, old surgical implants
NOTE: the MR scanner is a giant magnet!
MRI vs fMRI
MRI studies brain ANATOMY
- high resolution
fMRI studies brain FUNCTION
- low resolution
- BOLD = Blood Oxygenation Level Dependent
- As neural activity increases, blood oxygen increases, fMRI signal increases
Disorders or Consciousness
- Vegetative state: behavioral presentation of wakefulness in the absence of any evidence of awareness of self or environment
- Autonomic functions with preservation of cranial and spinal reflexes but no evidence of behavioral responses or language comprehension
- Distinct from coma (no wakefulness) on one side and minimally conscious state (response to environment, e.g. smooth pursuit) on other

CT Scan (CT=computer tomography)
Basic Principle of CT scan is to rotate machinery to take multiple x-rays with different paths thru the body
PROS:
widely available, very fast, cheaper than MRI, less hassle
CONS:
exposure to ionizing radiation (increased risk of cancer), poor tissue contrast, not versatile
CT IS BEST FOR AN EMERGENCY!!!!!
Nuclear Medicine: PET/SPECT Scan
PET = Positron Emission Tomography
Basic principle is to inject radioactive isotope attached to metabolic compound (oxygen, glucose, etc.) and WAIT for it to decay, looking for radioactive decay products
PROS:
fairly cheap, shows function (metabolism)
CONS:
exposure to ionizing radiation (increased rick of cancer), low resolution, slow to very slow, not versatile
EEG/MEG
EEG Basic principle: electrodes on scalp surface record summed electrical activity (mainly synaptic) of many neurons
(only difference w MEG is there aren’t electrodes on the scalp, there are SENSORS near scalp surface)
PROS:
completely non-invasive – this is the ONLY MODALITY THAT NEVER REQUIRES INJECTION OF A CONTRAST AGENT, no ionizing radiation, direct measurement of neuronal activity
CONS:
not really neuroimaging, limited clinical utility
EEG: sleep studies
MEG: epilepsy
