Brain Imaging of Drug Effects

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Brain Imaging of Drug Effects

• Electroencephalography (EEG)
• Positron Emission Tomography (PET)
• Magnetic Resonance Imaging (MRI)

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Outline
EEG
How is it useful in psychopharmacology?
PET
Examples of the technique at work
How does it work?
MRI
Downfalls of the technique
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Electroencephalography (EEG)

• Electro relating to electricity.
• Encephalo relating to the brain.
• Graphy writing or representation produced in a
  specified manner.
• Therefore, EEG produces a graphed representation
  of the electrical activity occurring in a
  persons brain.

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How does it work?
Electrodes are placed in specific regions of the
scalp. These electrodes measure the electrical
current occurring in varying regions of the brain
and transmit this information to a computer.
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Classifying EEG brain waves

• Frequency the number of oscillations/waves per
  second, measured in Hertz (Hz)
• reflects the firing rate of neurons
• alpha, beta, theta, delta
• Amplitude the magnitude of brain waves, measured
  in millivolts (mV), gives an indication of the
  waves power.
• The number of neurons firing in synchrony the
  distance between the neurons and the recording
  electrode

Different brain wave types can co-occur in
different regions of the brain.
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Delta Waves

• Slowest frequency waves 1 3 Hz
• Subjective feeling states
• deep, dreamless sleep, non-REM sleep, unconscious
• Associated tasks behaviors
• not moving, not attentive, sleeping

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Theta Waves

• Slow wave frequency 4 8 Hz
• Subjective feeling states
• Dreamlike, drowsy, distracted, unfocused
• Associated tasks behaviors
• State between wakefulness and sleep during
  sleep, meditation, internal focus, and prayer
  subconsciousness.

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Alpha Waves

• Mid wave frequency 8 - 13 Hz
• Subjective feeling states
• Awake but not actively processing information
  relaxed not agitated not drowsy tranquil
  calm
• Associated tasks behaviors
• Relaxing, watching television, light reading
  (e.g., novel), eyes closed.

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Beta Waves

• High wave frequency 12 - 35 Hz
• The normal dominant rhythm
• Subjective feeling states
• Alert, concentrating, attentive, focused, anxious
• Associated tasks behaviors
• listening and thinking during analytical problem
  solving, judgment, decision making, processing
  information, REM sleep!

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Using EEG in Psychopharmacology

• Correlate EEG activity with subjective state
• What waveform corresponds to particular
  drug-induced moods?
• Compare brain activity during drug-free baseline
  to that of drug-influenced activity
• Appearance of different drug-induced waveform
• Spikes in waveform amplitude (seizure activity)
• Stabilization of normal waveform fluctuations
• Classification of newly-developed drugs
• Similarities in frequency and amplitude to known
  drugs

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Using EEG in Psychopharmacology

• Assessing drug tolerance, cross-tolerance, and
  dependence across sessions
• Decreases in amplitude or frequency of waveforms
  suggest drug tolerance
• Cross-tolerance may occur following
  administration of different drugs of the same
  class
• Drug dependence can be quantified by correlating
  EEG recordings with withdrawal symptoms

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Correlating EEG activity with cocaine-induced
mood
Lukas (1991)
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Marijuana dependence and brain activity during
abstinence
Eyes closed

• Restlessness
• Insomnia
• Irritability
• Cognitive deficits

Hz
Herning, Better, Tate, Cadet (2003)
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Problems with EEG

• EEG is sensitive to time of day, season of the
  year, age of the participant, and recency of food
  intake.
• Limited diagnostic ability changes in brain wave
  activity could be due to things other than drug
  effects such as anxiety, fatigue, prayer, mood,
  or even a psychiatric disorder such as dementia,
  schizophrenia, depression, or borderline
  personality disorder.

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Positron Emission Tomography (PET)

• Positron the antiparticle (opposite
  corresponding particle) of an electron.
• Emission release or discharge of a substance
  into an environment.
• Tomography a series of detailed pictures of
  areas inside the body.

Therefore, PET scanning produces a detailed look
at the inside of the brain through the emission
of a positron.
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How does it work?

• PET scanning involves using isotopes, mainly of
  carbon, nitrogen, oxygen, and fluorine.
• These isotopes are radioactive, they are unstable
  and undergo rapid decay.

• During radioactive decay of an unstable atom, a
  proton is converted into a neutron, and a
  positron is emitted from the atoms nucleus.

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• Radioactive isotopes can be combined with a
  metabolically-active agent such as glucose,
  water, or a drug of abuse.
• If a stable carbon atom of a cocaine molecule is
  replaced with an unstable, radioactive carbon
  isotope, the resulting radiotracer decays by
  emitting a positron that can be detected in the
  brain by a PET scanner.

C17H21NO4
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Positron-electron annihilation gamma rays
Gamma rays are emitted from the brain at 180
degrees
Gamma rays hit scintillator crystals which light
up. This info is transmitted to a computer and
the origin of positron emission can be plotted
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Using PET in Psychopharmacology

• Directly measure brain distribution and activity
  of a wide variety of drug classes (e.g.,
  stimulants, opioids, hallucinogens, and others).
• Where do these drugs go in the brain and how do
  they act once theyre there?
• Determine drug receptor densities in various
  brain regions and keep track of changes that
  occur with various degrees of drug use
• How extensive are receptors for various drugs and
  how quickly to these receptors change with drug
  use?

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Using PET in Psychopharmacology

• Assess competition between radiotracers and
  neurotransmitters or drugs of abuse that occupy
  the same receptor sites.
• What percentage of receptor sites need to be
  occupied to produce subjective feelings of
  drug-induced euphoria?
• Isolate areas of the brain that are active during
  mental activities such as craving
• Measure metabolic activity using radioactive
  glucose and radioactive water

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Using PET in Psychopharmacology

• PET scanners for laboratory animals help in
  pre-clinical assessment of newly-developed drug
  treatments.
• New drugs can be made radioactive and monitored
  for drug absorption, distribution, and excretion.
• This reduces need for multiple animals used to
  examine brain tissue at various time points of
  drug action.

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PET imaging of DA transporter densities in the
striatum of baboons
Total dose over 8 hrs 2, 4, and 8 mg/kg Closely
approximates human binge episode
High DAT density
B
Low DAT density
Villemagne, Yuan, Wong, Dannals, Hatzidimitriou,
Mathews, Ravert, Musachio, McCann, Ricaurte The
Journal of Neuroscience (1998)
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Opiate craving in abstinent subjects

• Mean duration of abstinence 8 months
• Two 2-min scripts, one of an event involving
  strong craving for opiates, the other neutral.
• Injected 15OH2O (provides a measure
• of regional cerebral blood flow and metabolic
  activity).
• Increase in rCBF in an area overlying the left
  medial prefrontal region and adjacent left
  anterior cingulate cortex during playback of
  craving script.
• directing attention
• decision making
• judgment
• suppression of prepotent responses
• conditioned drug seeking
• craving

Daglish et al. (2001)
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Problems with PET

• Compared to newer technologies, PET offers a low
  degree of spatial resolution.
• Difficult to distinguish between two structures
  side by side
• Radioactive agents are administered into
  patients body
• One PET scan 70 chest x-rays.
• Expense because radiotracers decay so quickly,
  they must be made on-site in a cyclotron (cost of
  which is about 5 million)

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Magnetic Resonance Imaging (MRI)

• Magnetic having the properties of a magnet the
  ability to draw or pull.
• Resonance vibrations caused by the transfer of
  energy.
• Imaging any method used to produce a picture of
  internal body structures .
• Therefore, MRI uses magnets to cause
  positively-charge hydrogen molecules in the body
  to resonate to produce an image of the brain.

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How does it work?

• Hydrogen atoms are in constant motion, each
  spinning on its axis.
• This spinning produces the
• magnetic property of hydrogen.
• Hydrogen atoms have a large magnetic moment.
• Line up when placed in a magnetic field

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The magnetic of MRI
Superconducting magnet 40,000 times more
powerful than the earths pull.
Hydrogen atoms line up with the z-axis
While they are aligned, hydrogen atoms also
rotate or precess around the axis of the
externally-created magnetic field.
Hydrogen atoms precess at the same speed or
frequency but may be at any phase of their
precession at any given time.
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The resonance of MRI

• Resonance the transfer of energy, at a
  particular frequency, between two systems.

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We can do the same thing with hydrogen atoms

• In MRI, pulses of electromagnetic energy (called
  radiofrequency waves) are directed into the body
  at the exact frequency that causes hydrogen atoms
  to resonate.
• As protons resonate, they acquire the same phase
  of precession around the axis of the external
  magnetic field.

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• As protons resonate, the energy they absorb
  causes their angle of alignment with the z-axis
  to increase to 90 or even 180 degrees.
• When RF energy is turned off, the protons begin
  to go back to their 0 degree angle of alignment
  and begin dephasing, or rotating out of step.
• They release the excess energy that was stored
  when they were resonating which creates a signal
  that is picked up by the MRI machine and
  converted into a very detailed image.

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Using MRI in Psychopharmacology

• MRI allows researchers to construct a very
  detailed 3-D picture of the brain
• detect neuron loss and shrinkage of brain regions
• fMRI (functional MRI) can detect brain
  activation by measuring magnetic deoxygenated
  hemoglobin which is reduced when oxygen-rich
  blood flow increases to brain regions during high
  activity levels and metabolism.

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Nicotine abstinence and cognitive impairment -
fMRI
1-back S 2-back N 3-back Y
Y
N
S
X
Xu et al. (2005)
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MDMA (ecstasy) and hippocampal memory
Frequency 2.15 days/mo. Length of use 31 months
Daumann et al. (2005)
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Problems with MRI

• Expensive to purchase and operate.
• The bore of the scanner is small and can not
  accommodate very obese individuals.
• Once inside the bore, participants often report
  discomfort and anxiety with 1 of individuals
  experiencing severe claustrophobic or panic
  attacks.
• Patients must remain entirely motionless during
  the scan to prevent distorted/blurry images.
• Especially difficult if they are feeling anxious
  or uncomfortable

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Problems with MRI

• Metal objects can become dangerous flying
  projectiles .
• Aneurysm clips, some dental implants, heart
  pacemakers, fragments of metal in the eye, or
  newly-inserted staples can be sucked from the
  body or heated to scalding temperatures.
• Oxygen tanks, IV poles, heart monitors and other
  life-saving and life-monitoring equipment cannot
  enter the MRI room.
• Excludes patients on breathing machines, etc.
• The MRI room must be specially built with a
  reinforced floor and a magnetic shield to block
  inference from other sources of radiofrequency
  (e.g., FM radio!) that can be picked up and
  transmitted by the MRI machine.

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The future of neuroimaging looks bright