Career Choices in Medicine and Science

1
Career Choices in Medicine and Science
Studying Seizures to Understand Human
Consciousness

• Dario J. Englot
• Yale MD/PhD Program
• February 9, 2007

2
Careers in Medicine and Science

• Private practice medicine
• Academic medicine (MD or MD/PhD)
• Clinic-heavy
• Research-heavy
• Example my mentor, Hal Blumenfeld, MD, PhD
• Biological/physical sciences (PhD)
• Research-heavy
• Teaching-heavy
• Industry, Government
• Combinations

3
Training paths

• Clinical path (MD or DO)
• Research/Teaching-path (PhD)
• Combined path (MD/PhD)
• Finances, alternative paths

Med school (4 yrs) Residency (3-7 yrs)
Med Classes Clinical
Clinical
2yrs Rotations 2yrs
Rotations
PhD program (5-6 yrs) Post-doc(s)
(2-5 yrs)
Grad Classes/ Thesis Research
Research
Research 2yrs 3-4yrs
MD/PhD program (7-8 yrs)
Residency (3-7 yrs)
Med Grad Thesis Research
Clinical Clinical Research
Classes 2yrs 3-4yrs
Rotations 2yrs Rotations
4
Admission requirements

• Medical school
• Premed classes, competitive MCAT and GPA,
  volunteer and clinical experiences
• PhD program
• Significant research experience, competitive GRE
  and GPA
• MD/PhD
• All of above except only MCAT needed (not GRE)
• Average MCAT and GPA usually higher than MD-only

5
My experiences
6
What is the human mind?
Blumenfeld, 2002
7
Definitions

• Seizure abnormal rhythmic discharge in the brain
  associated with behavioral symptoms
• Generalized The whole brain
• Associated with loss of consciousness
• Eg., Tonic-clonic (grand mal), absence (petite
  mal)
• Partial Involves only a portion of the brain
• Simple Not associated with loss of consciousness
• Complex Associated with loss of consciousness
• Why?
• Eg., Temporal Lobe Epilepsy (TLE)

8
Temporal Lobe Epilepsy

• Recurrent unprovoked seizures originating from
  the temporal lobe
• Most common form of epilepsy
• Typical characteristics of complex-partial
  temporal lobe seizure wide-eyed, motionless
  stare, dilated pupils, and behavioral arrest.
  Oral alimentary automatisms such as lip smacking,
  chewing, and swallowing are also common.
• Aura (80) somatosensory, autonomic, and
  psychological phenomena
• Etiology infection, trauma, malignancy, vascular
  malformations, idiopathic
• Treatment Antiepileptic drugs (AEDs), vagal
  nerve stimulation, and surgical resection

9
Example of intracranial EEG recording during a
mesial temporal lobe seizure
Blumenfeld, H. et al. Neurology 2004631015-1021
10
Complex partial seizures arising from the
temporal lobe are associated with significant CBF
increases and decreases in widespread brain
regions
Blumenfeld, H. et al. Cereb. Cortex 2004
14892-902
11
Questions

• What is the mechanism of ictal slowing?
• Inhibitory process or suspended excitation
• Hippocampo-cortical or cortico-thalamic
• Which specific areas are affected?
• Need animal model!

12
The search for an animal model

• Electrical vs. pharmacological stimulation
• Kindling Daily stimulations of 1s train, 1ms
  pulses at 60Hz causes progressively worsening
  seizures
• 4-aminopyridine voltage gated K channel
  antagonist
• Amygdala vs. hippocampus
• Rat vs. guinea pig
• Awake-behaving vs. anesthetized
• With or without antiepileptic
• Where to record from

13
Protocol

• Anesthetize animal with ketamine/xylazine
• Stererotactially place recording and stimulating
  electrodes in dorsal hippocampus and recording
  electrode in orbital frontal cortex
• Allow anesthesia to lighten
• Breathing rate increases, slow waves disappear,
  but animal still motionless and non-responsive
• Stimulate 1s train of 1ms pulses at 60Hz
• Increase current to find threshold necessary to
  produce a 60s seizure

14
Limbic seizures are characterized by fast
polyspike activity in the hippocampus, and 1-2 Hz
large amplitude slow waves in the frontal cortex

• K132-stim27-CG-BaselineANDSz.jpg

A
B
15
(No Transcript)
16
Both low- and high-frequency signal power
increases in the hippocampus ictally, while in
the frontal cortex, low-frequency power increases
and high-frequency power decreases
17
Frontal slow waves present during the deeply
anesthetized state resemble neocortical slowing
seen during limbic seizures
18
Test
Low- and high-frequency power under light
anesthesia, during seizure, postically, and under
deep anesthesia.
19
While seizure activity in the hippocampus leads
to an increase in CBF, frontal neocortical
slowing is associated with a decrease in CBF.
20
Conclusions

• Our methods may provide a good animal model of
  complex-partial temporal lobe seizures with
  neocortical slowing
• Ictal neocortical slowing is characterized by
  large amplitude slow waves and a burst-like
  firing pattern resembling the deeply anesthetized
  state and normal cortical slow oscillations
• Is the seizure in the hippocampus causing or
  allowing the frontal cortex to go to sleep?

21
Remaining questions and future directions

• Which specific areas are affected by this
  slowing? Which of these areas are involved in
  consciousness and awareness?
• More electrophysiology and fMRI recordings
• Behavioral tests in awake-behaving animals during
  the seizures
• What is the mechanism? How and why do
  complex-partial seizures lead to neocortical
  slowing?
• Requires further network characterization
• Continue research of human patients undergoing
  epilepsy evaluation
• PhD dissertation in science putting together
  and fleshing out a story

22
Thank you

• At Yale Dr. Hal Blumenfeld
• Dr. Ulrich Schridde
• At Scranton Dr. Tim Cannon
• Dr. Mary Engel