Brain Imaging of Drug Effects

EEG

PET

MRI

How is it useful in psychopharmacology?

Examples of the technique at work

Downfalls of the technique

How does it work?

Electroencephalography Electroencephalography (EEG)(EEG)

ElectroElectro: relating to electricity.: relating to electricity. EncephaloEncephalo: relating to the brain.: relating to the brain. GraphyGraphy: writing or representation : writing or representation

produced in a specified manner.produced in a specified manner.

Therefore, EEG produces a graphed Therefore, EEG produces a graphed representation of the electrical representation of the electrical activity occurring in a person’s brain.activity occurring in a person’s brain.

How does it work?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.

Classifying EEG brain Classifying EEG brain waveswaves FrequencyFrequency: the number of oscillations/waves per : the number of oscillations/waves per

second, measured in Hertz (Hz)second, measured in Hertz (Hz) reflects the firing rate of neuronsreflects the firing rate of neurons alpha, beta, theta, deltaalpha, beta, theta, delta

AmplitudeAmplitude: the magnitude of brain waves, measured : the magnitude of brain waves, measured in millivolts (mV), gives an indication of the wave’s in millivolts (mV), gives an indication of the wave’s “power”.“power”. The number of neurons firing in synchrony & the The number of neurons firing in synchrony & the

distance between the neurons and the recording distance between the neurons and the recording electrodeelectrodeDifferent brain wave types can co-occur in different regions of the brain.

Delta WavesDelta Waves

Slowest frequency Slowest frequency waves: 1 – 3 Hzwaves: 1 – 3 Hz

Subjective feeling states:Subjective feeling states: deep, dreamless sleep, non-deep, dreamless sleep, non-

REM sleep, unconsciousREM sleep, unconscious Associated tasks & Associated tasks &

behaviors:behaviors: not moving, not attentive, not moving, not attentive,

sleepingsleeping

Theta WavesTheta Waves

Slow wave frequency: 4 – 8 HzSlow wave frequency: 4 – 8 Hz Subjective feeling states: Subjective feeling states:

Dreamlike, drowsy, distracted, Dreamlike, drowsy, distracted, unfocusedunfocused

Associated tasks & behaviors:Associated tasks & behaviors: State between wakefulness and sleep; State between wakefulness and sleep;

during sleep, meditation, internal during sleep, meditation, internal focus, and prayer; subconsciousness.focus, and prayer; subconsciousness.

Alpha WavesAlpha Waves

Mid wave frequency: 8 - 13 Mid wave frequency: 8 - 13 HzHz

Subjective feeling states: Subjective feeling states: Awake but not actively processing Awake but not actively processing

information; relaxed; not agitated; information; relaxed; not agitated; not drowsy; tranquil & calmnot drowsy; tranquil & calm

Associated tasks & Associated tasks & behaviors:behaviors: Relaxing, watching television, Relaxing, watching television,

light reading (e.g., novel), eyes light reading (e.g., novel), eyes closed.closed.

Beta WavesBeta Waves High wave frequency: 12 - 35 High wave frequency: 12 - 35

HzHz The “normal” dominant rhythmThe “normal” dominant rhythm

Subjective feeling states: Subjective feeling states: Alert, concentrating, attentive, Alert, concentrating, attentive,

focused, anxiousfocused, anxious Associated tasks & behaviors:Associated tasks & behaviors:

listening and thinking during listening and thinking during analytical problem solving, analytical problem solving, judgment, decision making, judgment, decision making, processing information, REM processing information, REM sleep!sleep!

Using EEG in Using EEG in PsychopharmacologyPsychopharmacology

Correlate EEG activity with subjective state Correlate EEG activity with subjective state What waveform corresponds to particular drug-What waveform corresponds to particular drug-

induced moods?induced moods? Compare brain activity during drug-free Compare brain activity during drug-free

baseline to that of drug-influenced activitybaseline to that of drug-influenced activity Appearance of different drug-induced waveformAppearance of different drug-induced waveform Spikes in waveform amplitude (seizure activity)Spikes in waveform amplitude (seizure activity) Stabilization of normal waveform fluctuationsStabilization of normal waveform fluctuations

Classification of newly-developed drugsClassification of newly-developed drugs Similarities in frequency and amplitude to known Similarities in frequency and amplitude to known

drugsdrugs

Assessing drug tolerance, cross-Assessing drug tolerance, cross-tolerance, and dependence across tolerance, and dependence across sessionssessions Decreases in amplitude or frequency of Decreases in amplitude or frequency of

waveforms suggest drug tolerancewaveforms suggest drug tolerance Cross-tolerance may occur following Cross-tolerance may occur following

administration of different drugs of the same administration of different drugs of the same classclass

Drug dependence can be quantified by Drug dependence can be quantified by correlating EEG recordings with withdrawal correlating EEG recordings with withdrawal symptomssymptoms

Using EEG in Using EEG in PsychopharmacologyPsychopharmacology

Correlating EEG activity with Correlating EEG activity with cocaine-induced moodcocaine-induced mood

delta

theta

alpha

Lukas (1991)

Marijuana dependence and Marijuana dependence and brain activity during brain activity during

abstinenceabstinence

Herning, Better, Tate, & Cadet (2003)

log

(p

ow

er)

1-4 4-8 8-10 13-2510-13 25-50

control group72-hr abstinence28-day abstinence

*

*

*

*

Eyes closed

Hz

- Restlessness- Insomnia- Irritability - Cognitive deficits

Problems with EEGProblems with EEG

EEG is sensitive to time of day, season EEG is sensitive to time of day, season of the year, age of the participant, and of the year, age of the participant, and recency of food intake.recency of food intake.

Limited diagnostic ability: changes in Limited diagnostic ability: changes in brain wave activity could be due to brain wave activity could be due to things other than drug effects such as things other than drug effects such as anxiety, fatigue, prayer, mood, or anxiety, fatigue, prayer, mood, or even a psychiatric disorder such as even a psychiatric disorder such as dementia, schizophrenia, depression, dementia, schizophrenia, depression, or borderline personality disorder.or borderline personality disorder.

Positron Emission Tomography Positron Emission Tomography (PET)(PET)

PositronPositron: the antiparticle (opposite : the antiparticle (opposite corresponding particle) of an corresponding particle) of an electron. electron.

EmissionEmission: release or discharge of a : release or discharge of a substance into an environment.substance into an environment.

TomographyTomography: a series of detailed : a series of detailed pictures of areas inside the body. pictures of areas inside the body.

Therefore, PET scanning Therefore, PET scanning produces produces a detailed look at the inside of a detailed look at the inside of the brain through the the brain through the emission of a positron.emission of a positron.

How does it work?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 atom’s nucleus.

Radioactive isotopes can be combined with Radioactive isotopes can be combined with a metabolically-active agent such as a metabolically-active agent such as glucose, water, or a drug of abuse.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

Positron-electron annihilation =

gamma rays Gamma raysare emitted from thebrain 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

Using PET in Using PET in PsychopharmacologyPsychopharmacology

Directly measure brain distribution and Directly measure brain distribution and activity of a wide variety of drug classes activity of a wide variety of drug classes (e.g., stimulants, opioids, hallucinogens, (e.g., stimulants, opioids, hallucinogens, and others).and others). Where do these drugs go in the brain and Where do these drugs go in the brain and

how do they act once they’re there?how do they act once they’re there? Determine drug receptor densities in Determine drug receptor densities in

various brain regions and keep track of various brain regions and keep track of changes that occur with various degrees changes that occur with various degrees of drug useof drug use How extensive are receptors for various How extensive are receptors for various

drugs and how quickly to these receptors drugs and how quickly to these receptors change with drug use? change with drug use?


Assess competition between radiotracers Assess competition between radiotracers and neurotransmitters or drugs of abuse and neurotransmitters or drugs of abuse that occupy the same receptor sites.that occupy the same receptor sites. What percentage of receptor sites need to be What percentage of receptor sites need to be

occupied to produce subjective feelings of occupied to produce subjective feelings of drug-induced euphoria?drug-induced euphoria?

Isolate areas of the brain that are active Isolate areas of the brain that are active during mental activities such as cravingduring mental activities such as craving Measure metabolic activity using radioactive Measure metabolic activity using radioactive

glucose and radioactive waterglucose and radioactive water


PET scanners for PET scanners for laboratory animals help in laboratory animals help in pre-clinical assessment of pre-clinical assessment of newly-developed drug newly-developed drug treatments.treatments. New drugs can be made New drugs can be made

radioactive and monitored radioactive and monitored for drug absorption, for drug absorption, distribution, and excretion.distribution, and excretion.

This reduces need for This reduces need for multiple animals used to multiple animals used to examine brain tissue at examine brain tissue at various time points of drug various time points of drug action.action.

PET imaging of DA transporter PET imaging of DA transporter densities densities

in the striatum of baboonsin the striatum of baboons

Villemagne, Yuan, Wong, Dannals, Hatzidimitriou, Mathews, Ravert, Musachio, McCann, RicaurteThe Journal of Neuroscience (1998)

A

B

Total dose over 8 hrs:2, 4, and 8 mg/kg

Closely approximates human binge episode

Low DATdensity

High DAT density

Opiate craving in abstinent Opiate craving in abstinent subjectssubjects

Mean duration of abstinence: 8 months

Two 2-min scripts, one of an event involving strong craving for opiates, the other neutral.

Injected [15O]H2O (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)

Problems with PETProblems with PET

Compared to newer technologies, PET Compared to newer technologies, PET offers a low degree of spatial resolution.offers a low degree of spatial resolution. Difficult to distinguish between two Difficult to distinguish between two

structures side by sidestructures side by side Radioactive agents are administered Radioactive agents are administered

into patient’s bodyinto patient’s body One PET scan = 70 chest x-rays.One PET scan = 70 chest x-rays.

Expense: because radiotracers decay so Expense: because radiotracers decay so quickly, they must be made on-site in a quickly, they must be made on-site in a cyclotron cyclotron (cost of which is about $5 (cost of which is about $5 million)million)

Magnetic Resonance Magnetic Resonance Imaging (MRI)Imaging (MRI)

MagneticMagnetic: having the properties of a magnet; : having the properties of a magnet; the ability to draw or pull.the ability to draw or pull.

ResonanceResonance: vibrations caused by the transfer : vibrations caused by the transfer of energy.of energy.

ImagingImaging: any method used to produce a : any method used to produce a picture of internal body structures .picture of internal body structures .

Therefore, MRI uses magnets to cause Therefore, MRI uses magnets to cause positively-charge hydrogen molecules in the positively-charge hydrogen molecules in the body to resonate to produce an image of the body to resonate to produce an image of the

brain.brain.

How does it work?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

Superconducting magnet – 40,000 times more powerful than the earth’s 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.

The “magnetic” The “magnetic” of MRIof MRI

The “resonance” of MRIThe “resonance” of MRI Resonance: the transfer of energy, at a Resonance: the transfer of energy, at a

particular frequency, between two particular frequency, between two systems.systems.

We can do the same thing We can do the same thing with hydrogen atomswith hydrogen atoms

In MRI, pulses of electromagnetic In MRI, pulses of electromagnetic energy (called radiofrequency energy (called radiofrequency waves) are directed into the body at waves) are directed into the body at the exact frequency that causes the exact frequency that causes hydrogen atoms to resonate. hydrogen atoms to resonate.

As protons resonate, they acquire As protons resonate, they acquire the same phase of precession around the same phase of precession around the axis of the external magnetic the axis of the external magnetic field.field.

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.

Using MRI in Using MRI in PsychopharmacologyPsychopharmacology

MRI allows researchers to construct a MRI allows researchers to construct a very detailed 3-D picture of the brainvery detailed 3-D picture of the brain detect neuron loss and shrinkage of brain detect neuron loss and shrinkage of brain

regionsregions fMRI (functional MRI) can detect brain fMRI (functional MRI) can detect brain

activation by measuring magnetic activation by measuring magnetic deoxygenated hemoglobin which is deoxygenated hemoglobin which is reduced when oxygen-rich blood flow reduced when oxygen-rich blood flow increases to brain regions during high increases to brain regions during high activity levels and metabolism.activity levels and metabolism.

Nicotine abstinence and Nicotine abstinence and cognitive impairment - cognitive impairment -

fMRIfMRI

YNSX1-back = S2-back = N3-back = Y

Xu et al.(2005)

MDMA (ecstasy) and hippocampal MDMA (ecstasy) and hippocampal memorymemory

accountant barista carpenter

diver electrician florist

geologist hypnotist innkeeper

Frequency:2.15 days/mo.

Length of use:31 months

Daumann et al. (2005)

Problems with MRIProblems with MRI Expensive to purchase and operate.Expensive to purchase and operate. The bore of the scanner is small and can not The bore of the scanner is small and can not

accommodate very obese individuals.accommodate very obese individuals. Once inside the bore, participants often report Once inside the bore, participants often report

discomfort and anxiety with 1% of individuals discomfort and anxiety with 1% of individuals experiencing severe claustrophobic or panic experiencing severe claustrophobic or panic attacks.attacks.

Patients must remain entirely motionless during Patients must remain entirely motionless during the scan to prevent distorted/blurry images.the scan to prevent distorted/blurry images. Especially difficult if they are feeling anxious or Especially difficult if they are feeling anxious or

uncomfortableuncomfortable

Problems with MRIProblems with MRI Metal objects can become dangerous flying Metal objects can become dangerous flying

projectiles .projectiles . Aneurysm clips, some dental implants, heart Aneurysm clips, some dental implants, heart

pacemakers, fragments of metal in the eye, or pacemakers, fragments of metal in the eye, or newly-inserted staples can be sucked from the newly-inserted staples can be sucked from the body or heated to scalding temperatures.body or heated to scalding temperatures.

Oxygen tanks, IV poles, heart monitors and Oxygen tanks, IV poles, heart monitors and other life-saving and life-monitoring equipment other life-saving and life-monitoring equipment cannot enter the MRI room.cannot enter the MRI room. Excludes patients on breathing machines, etc.Excludes patients on breathing machines, etc.

The MRI room must be specially built with a The MRI room must be specially built with a reinforced floor and a magnetic shield to block reinforced floor and a magnetic shield to block inference from other sources of radiofrequency inference from other sources of radiofrequency (e.g., FM radio!) that can be picked up and (e.g., FM radio!) that can be picked up and transmitted by the MRI machine.transmitted by the MRI machine.

The future of neuroimaging The future of neuroimaging

looks brightlooks bright

Brain Imaging of Drug Effects

Documents

Transcript of Brain Imaging of Drug Effects