Functional Magnetic

Resonance Imaging
of Human Brain
Activity with Drug
Addiction
REFERAT
PEMBIMBING : DR. YOPI SIMARGI, SP.RAD.
Department of Radiology
School of Medicine Atma Jaya Catholic University of Indonesia
Jakarta 2016

Oleh :

Jessy Claudia

2014 061 061

Swastiko Wiweka Adi

2014 061 063

Jesica Tatang

2015 061 019

Vincentius Henry Sundah

2015 061 023

Eldaa Prisca Refianti Sutanto

2015 061 024

Jemmy Gunawan

2015 061 026

Pendahuluan 1

Structural MRI

Structural brain MRI provides information of location, shapes, and sizes of

the brains various regions and sub-regions

It also can demonstrate the presence of abnormal tissue and changes in

tissue composition

Functional MRI

Functional MRI detects changes in the local magnetic field that occur as
a result of changes in the ratio of oxygenated to deoxygenated
hemoglobin in arterial blood vessels in specific brain regions during a
cognitive task

Perbedaan MRI & fMRI

Structural magnetic resonance
imaging (MRI)

Map tissue morphology, composition

Functional magnetic
resonance imaging (fMRI)

Visualize changes in oxygenation and

blood flow associated with brain
activities

Definisi Adiksi

Addiction is defined as a chronic, relapsing brain disease that is

characterized by compulsive drug seeking and use, despite harmful
consequences.

It is considered a brain disease because drugs change the brain; they

change its structure and how it works.

Imaging in Drug Addiction

Detecting structural and functional brain changes of the addiction

patients through MRI & fMRI

Anatomi Otak
pada MRI 2

Alkohol 3

GENDER EFFECTS IN
ALCOHOL DEPENDENCE: AN
FMRI PILOT STUDY
EXAMINING AFFECTIVE
PROCESSING

Alcohol Addiction (1)

Alcohol dependence (AD) has global effects on brain structure and

function, including frontolimbic regions regulating affective processing.

Preliminary evidence suggests alcohol blunts limbic response to negative

affective stimuli and increases activation to positive affective stimuli.

Alcohol Addiction (2)

Fourteen abstinent AD individuals (8 F, 6 M) and 14 healthy controls (9 F, 5

M), ages 23 to 60, were included in this facial affective processing
functional magnetic resonance imaging pilotstudy.

Whole-brain linear regression analyses were performed, and follow-up

analyses examined

Alcohol Addiction (3)

Fearful condition-The AD group demonstrated reduced activation in the

right medial frontal gyrus, compared with controls. Gender moderated
the effects of AD in bilateral inferior frontal gyri.

Happy condition-AD individuals had increased activation in the right

thalamus. Gender moderated the effects of AD in the left caudate, right
middle frontal gyrus, left paracentral lobule, and right lingual gyrus.

Interactive AD and gender effects for fearful and happy faces were such
that AD men activated more than control men, but AD women activated
less than control women.

Enhanced coping was associated with greater activation in right medial

frontal gyrus during fearful condition in AD individuals.

Right medial frontal gyrus

Group differences in right medial frontal

blood oxygen level dependent activation
to fearful versus neutral faces. AD, alcoholdependent individuals.

Inferior frontal gyri

Left Thalamus

Group differences in left thalamus blood

oxygen level dependent activation for
happy versus neutral faces. AD = alcoholdependent individuals.

Right middle
frontal gyrus, left
paracentral
lobule, left
caudate, and
right lingual gyrus
Interactive effects of
group and gender on
left middle frontal,
paracentral, caudate,
and right lingual blood
oxygen level
dependent activation
during happy versus
neutral faces. AD =
alcohol dependent.

Enchanced coping right medial frontal

Increased planful problem solving is

related to greater blood oxygen level
dependent activation in the right medial
frontal gyrus in AD individuals during
processing of fearful versus neutral faces.
AD = alcohol-dependent individuals.

Cocaine &
Cannabis

The Role of Dopamine 4

Neurochemical studies large and fast increases in dopamine are

associated with the reinforcing effects of drugs of abuse, but also that
after chronic drug abuse and during withdrawal, brain dopamine
function is markedly decreased and these decreases are associated
with dysfunction of prefrontal regions
The changes in brain dopamine function
1.
decreased sensitivity to natural reinforcers since dopamine also
mediates the reinforcing effects of natural reinforcers, and
2.
disruption of frontal cortical functions, such as inhibitory control
and salience attribution.

Functional imaging
studies have shown that
during drug intoxication,
or during craving, these
frontal regions become
activated as part of a
complex pattern that
includes brain circuits
involved with reward
(nucleus accumbens),
motivation (orbitofrontal
cortex), memory
(amygdala and
Meso-cortic pathway
hippocampus), and
Meso-limbic pathway
cognitive control
(prefrontal cortex and
Nigrostriatal pathway
4
cingulate gyrus)

Cocaine 5

1. Dopamine
Cocaine
transporters blocker

2.Inhibit
dopamine
reuptake
By binding to the
active site of the
transporter

3. Increase
lifetime of
dopamine
Increase augments
overabundance of
Dopamine

Presynaptic adrenergic pathway

Functional Brain Imaging

Identify specific brain regions that become active with
presentation of drug-use cues and/or with the experience of
craving 6
fMRI based on the measurement of the changes in
magnetic properties in neuronal tissue
Activation signal generated from fMRI results from differences in
the magnetic properties of oxygenated versus deoxygenated
hemoglobin (blood oxygen level dependent contrast). 5
During activation of a brain region there is an excess of arterial
blood delivered into the area, with concomitant changes in
the ratio of deoxyhemoglobin to oxyhemoglobin.

Cocaine-induced BOLD activation in drug na ve and cocaine pretreated rats. (a) Representative high-resolution
anatomical images showing regions of interest. Numbers indicate the following regions: (1) dorsal prefrontal cortex (dPFC);
(2) medial prefrontal cortex (mPFC); (3) agranular insular cortex (AIC); (4) anterior cingulate cortex (Cg); (5) dorsal striatum
(Str); (6) nucleus accumbens (NAC); (7) ventral pallidum (VP); (8) somatosensory cortex (SSC); (9) globus pallidus (GP); (10)
dorsomedial thalamus (DMT); (11) ventroposterolateral thalamus (VPL); (12) hippocampus (Hip); (13) substantia nigra (SN);
(14) ventral tegmental area (VTA); (15) periaqueductal grey (PAG); (16) raphe (Rph). (b) Average BOLD responses to
cocaine in brain areas depicted in (a). Data are averages of the first 5 min after ICV cocaine injections and expressed as
mean7SEM. *denotes po0.05 comparing saline vs cocaine pretreated. Numbers along the x-axis indicate the brain areas
depicted in (a).5

Images of coronal sections

obtained with fMRI, showing
areas of brain activation
and deactivation during
cocaine intoxication compared with those after saline
administration. During
intoxication there is a
complex pattern of
activation and/or
deactivation that includes
the ventral tegmental area
(VTA) and the substantia
nigra (SN), where DA cells
are located, as well as
regions involved with reward
(nucleus accumbens, NAc;
basal forebrain, BF; globus
pal- lidus, GP), with memory
(amygdala), and with
motivation (subcal- losal
cortex, SCC). The color scale
indicates the level of
significance (P value) of the
change in activation of the
bold signal. Reproduced
with permission from
Neuron.5

Cannabis 7

Individuals with high tonic levels of dopamine (i.e. carriers of CT/TT

genotypes) would be more sensitive to the impairing potential of
cannabis and cocaine on cognitive im- pulse control because they would
experience a drug induced hyperdopaminergic state.

Induced dopaminergic stimulation of the NAc following both drugs would

reduce functional corticostriatal connectivity

Cannabis as well as cocaine significantly reduced functional connectivity

with NAc seeds in both hemispheres, relative to placebo

NAc related
functional
connectivity
decrements
following cannabis
and cocaine in the
left and right
hemisphere, relative
to placebo. Shown
are thresholded (t =
2.34) Z-score maps
of functional
connectivity (a)
averaged over DBH
genotypes and (b)
for individuals with
CC and CT/TT
genotypes
separately (CAN =
cannabis, COC =
cocaine; left = left;
planes are made at
MNI seed position) 7

NAc related functional

connectivity decrements as
a function of cannabis x DBH
and cocaine x DBH
interactions in the left (LH)
and right hemisphere (RH),
(CAN = cannabis, COC =
cocaine; left = left; planes
are made at MNI seed
position)7

METHAMPHETAMINE

Metamphetamine (1)

Meningkatkan konsentrasi: dopamin, norepinefrin, dan serotonin.

Mekanisme 8 :

Menempel pada membran neuron presinaps terminal dan secara langsung menginduksi
pelepasan dopamin

Berinteraksi dengan vesikel presinaps yang berisi dopamin (via VMAT-2), mengakibatkan
keluarnya dopamin dari vesikel ke sitosol neuron presinaps (menghambat penyimpanan
dopamin di dalam vesikel)

Berikatan dengan dopamine re-uptake transporter (DAT) secara kompetitif dengan dopamin,
mengakibatkan fungsi reuptake tidak berjalan

Pada dosis besar, dapat berikatan dengan monoamine oxidase (MAO) di neuron presinaps,
sehingga fungsi degradasi dopamin oleh MAO tidak terjadi konsentrasi dopamin yang tinggi
di presinaps

Selektif terhadap neuron serotonin pelepasan serotonin yang banyak dan menghambat
reuptake serotonin pada presinaps dengan reversal dari fungsi serotonin transporter (SERT)
berkumpul di ruang sinaps

Metamphetamine (2)

Penggunaan amfetamin secara berulang dalam waktu yang lama akan

menyebabkan berkurangnya cadangan katekolamin (prekursor
norepinefrin maupun dopamin).8

Amfetamin juga berpengaruh pada asetilkolin, substansi P, opioida

endogen, dan GABA menimbulkan perubahan metabolisme dan
aliran darah dalam otak, terutama pada prefrontal, frontal, temporal,
dan subkortikal.8

Metamphetamine (3)

Chang et al.9

Pengguna METH:

Decreased relative rCBF bilaterally in putamen/insular cortices and the right lateral parietal
brain region

Increased relative rCBF bilaterally in the left temporoparietal white matter, the left occipital
brain region and the right posterior parietal region.

Vollm et al.10

Administrasi METH mengaktivasi korteks orbitofrontal medial, the rostral part of anterior
cingulate cortex, dan ventral striatum mengaktivasi classical reward circuitry

Sumber: Vllm BA, de Araujo IE, Cowen PJ, Rolls ET, Kringelbach ML, Smith KA, et al. Methamphetamine activates reward circuitry in drug
nave human subjects. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2004 Sep;29(9):171522.

Metamphetamine (4)

Paulus et. Al11 :

Hubungan antara disfungsi pembuatan keputusan dan aktivasi neural di

area prefrontal yang berbeda.

Activated less of the dorsolateral prefrontal cortex (Brodmanns area [BA]

9) and failed to activate any of the ventromedial cortex (BA 10, BA11)

Showed less task-related activation in the orbitofrontal cortex (BA 10),

dorsolateral prefrontal cortex (BA 9), anterior cingulate (BA 32) and
parietal cortex (BA 7)

Volume-thresholded t-score renderings of the task-related activation in normal comparison (A D) and

metamphetamine-dependent subjects (E H).11

MDMA
(ECSTASY)

Tabel 1. Functional Neuroimaging in

MDMA Users 12

Sumber: Jager G,
de Win MML, van
der Tweel I, Schilt
T, Kahn RS, van
den Brink W, et al.
Assessment of
cognitive brain
function in
ecstasy users and
contributions of
other drugs of
abuse: results
from an FMRI
study.
Neuropsychophar
macol Off Publ
Am Coll
Neuropsychophar
macol. 2008
Jan;33(2):247
58.13

Sumber : Moeller
FG, Steinberg JL,
Dougherty DM,
Narayana PA,
Kramer LA,
Renshaw PF.
Functional MRI
study of working
memory in MDMA
users.
Psychopharmacol
ogy (Berl). 2004
Dec 1;177(1
2):18594.14

OPIOID 15

History and Terminology of Opioid

Opium is extracted from

poppy seeds (Paper
somniforum)

opium is a Greek word

meaning juice, or the
exudate from the poppy

opiate is a drug
extracted from the
exudate of the poppy

opioid is a natural or
synthetic drug that binds
to opioid receptors
producing agonist effects

Natural opioids occur in 2 places

In the juice of the opium poppy (morphine and codeine)

As endogenous endorphins

All other opioids are prepared from either morphine

(semisynthetic opioids such as heroin) or they are synthesized
from precursor compounds (synthetic opioids such as fentanyl)

Agonists
Morphine
Heroin
Hydromorphone
Fentanyl
Codeine

Antagonists

Naloxone
Naltrexone

Pharmacological Effects
Sedation and
anxiolysis
Gastrointestinal
symptoms

Depression of
respiration

Nausea and
vomiting

Cough
suppression
Pupillary
constriction

Mechanism of
action (1)

Mechanism of
action (2)

Mechanism of action (3)

Mechanism of action (4)

Activation of peripheral nociceptive fibers causes release of substance P

and other pain-signaling neurotransmitters from nerve terminals in the
dorsal horn of the spinal cord

Release of pain-signaling neurotransmitters is regulated by endogenous

endorphins or by exogenous opioid agonists by acting presynaptically to
inhibit substance P release, causing analgesia

Primary Effect of Opioid Receptor Activation

Reduction or inhibition of neurotransmission, due largely to opioidinduced presynaptic inhibition of neurotransmitter release

Involves changes in transmembrane ion conductance

Increase potassium conductance (hyperpolarization)

Inactivation of calcium channels

Three Opioid Receptors

Mu ()
Kappa ()
Delta ()

Mu-Receptor: Two Types

Mu-1

Mu-2

Located outside spinal cord

Located throughout CNS

Responsible for central interpretation of

pain

Responsible for respiratory depression,

spinal analgesia, physical
dependence, and euphoria

Kappa Receptor

Only modest analgesia

Little or no respiratory depression

Little or no dependence

Dysphoric effects

Delta Receptor

It is unclear what delta s responsible for.

Delta agonists show poor analgesia and little addictive potential

May regulate mu receptor activity

Opioid Reseptor
Receptor

Effect
Analgesia (medial thalamus)
Euphoria

Mu

Sedation
Respiratory Depression (medulla)
Constipation (GI tract)
Analgesia (medial thalamus)

Kappa

Sedation
Diuresis

Delta

Supraspinal analgesia (medial thalamus)

Mu and Kappa Receptor Activation

Response
Analgesia
Respiratory Depression
Euphoria
Dysphoria
Decrease GI motility
Physical Dependence

Mu-1

Mu-2

Kappa

Mu and Kappa Receptors

DRUGS

MU

KAPPA

Pure Agonists

Agonist

Agonist

Agonist-Antagonist

Antagonist

Agonist

Pure Antagonists

Antagonist

Antagonist

Imaging in
Opioid
addiction

Structural Changes

Main alteration on opioid addiction patients are decrease white matter

in:

Amygdala

Internal & external capsules

Genu mid body of the corpus callosum

Functional Changes

Main alteration on opioid addiction patients are decrease functional

connectivity in:

anterior insula,

Amygdala

Nucleus accumbens

Psilocybin

Psilocybin (1)

Psilocybin komponen halusinogen utama pada magic mushroom

dan obat psychedelic klasik.16-17

Healing Ceremonies

Psikoterapi

Efek tergantung dosis

Psilocybin (2)

Produksi toksin Psilocybin efek neurotoksik mirip dengan LSD

berkaitan erat dengan serotonin.16-17

Berinteraksi dengan reseptor 5-HT

5-HT2A

5-HT1A

Robin et al : penurunan aliran darah dalam otak penurunan aktivitas

dan konektivitas otak.17

ASL Perfusion fMRI

BOLD fMRI

LSD

LSD (1)

Lysergic acid dietylamide (LSD) halusinogen sintetis. (obat psikiatrik

eksperimental tahun 1950).16

Penggunaan secara oral dengan manifestasi muncul dalam 30 menit

dan bertahan 8 sampai 10 jam.16

LSD (2)

LSD bekerja sebagai agonis parsial pada reseptor serotonin perubahan

mental status, mood dan persepsi.16,18

Efek mirip dengan MDMA, dengan gejala simpatometik yang dominan.

Kerusakan pada serotonergik neuronal akibat stres oksidatif.16,18

Daftar Pustaka (1)

1.

Fowler J, Volkow N, Kassed C, Chang L. Imaging the Addicted Human

Brain. Sci Pract Perspect 2007;3(2):4-16.

2.

Moeller TB, Reif E. Pocket Atlas of Sectional Anatomy: Computed

Tomography and Magnetic Resonance Imaging. Vol. 1. Ed ke-3. Stuttgart:
Thieme; 2007.

3.

Padula CB, Anthenelli RM, Eliassen JC, Nelson E, Lisdahl KM. Gender
effects in alcohol dependence: an fMRI pilot study examining affective
processing. Alcohol Clin Exp Res 2015;39(2):27281.

Daftar Pustaka (2)

4.

Volkow ND, Fowler JS, Wang G-J. The addicted human brain: insights from
imaging studies. J Clin Invest 2003;111(10):144451.

5.

Febo M, Segarra AC, Nair G, Schmidt K, Duong TQ, Ferris CF. The Neural
Consequences of Repeated Cocaine Exposure Revealed by Functional MRI in
Awake Rats. Neuropsychopharmacology 2005;30(5):93643.

6.

Wexler BE, Gottschalk CH, Fulbright RK, Prohovnik I, Lacadie CM, Rounsaville
BJ, et al. Functional magnetic resonance imaging of cocaine craving. Am J
Psychiatry 2001;158(1):8695.

7.

Ramaekers JG, van Wel JH, Spronk D, Franke B, Kenis G, Toennes SW, et al.
Cannabis and cocaine decrease cognitive impulse control and functional
corticostriatal connectivity in drug users with low activity DBH genotypes. Brain
Imaging Behav 2016;10(4):125463

Daftar Pustaka (3)

8.

Joewana, Satya. Gangguan Mental dan Perilaku Akibat Penggunaan Zat

Psikoaktif. Jakarta: EGC; 2004.

9.

Toolaney GH. New Research on Methamphetamine Abuse. Nova Publishers;

2006. Hal 208.

10.

Vllm BA, de Araujo IE, Cowen PJ, Rolls ET, Kringelbach ML, Smith KA, et al.
Methamphetamine activates reward circuitry in drug nave human subjects.
Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 2004
Sep;29(9):171522.

11.

Paulus MP, Hozack NE, Zauscher BE, Frank L, Brown GG, Braff DL, et al.
Behavioral and functional neuroimaging evidence for prefrontal dysfunction in
methamphetamine-dependent subjects. Neuropsychopharmacol Off Publ Am
Coll Neuropsychopharmacol 2002 Jan;26(1):5363.

Daftar Pustaka (4)

12.

Cowan RL. Neuroimaging research in human MDMA users: a review.

Psychopharmacology (Berl) 2007 Jan 1;189(4):53956.

13.

Jager G, de Win MML, van der Tweel I, Schilt T, Kahn RS, van den Brink W,
et al. Assessment of cognitive brain function in ecstasy users and
contributions of other drugs of abuse: results from an FMRI study.
Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 2008
Jan;33(2):24758.

14.

Moeller FG, Steinberg JL, Dougherty DM, Narayana PA, Kramer LA,
Renshaw PF. Functional MRI study of working memory in MDMA users.
Psychopharmacology (Berl)2004 Dec 1;177(12):18594.

Daftar Pustaka (5)

15.

Upadhyay J, Maleki N, Potter J, Elman I, Rudrauf D, Knudsen J, et al.

Alterations in brain structure and functional connectivity in prescription
opioid-dependent patients. Brain 2010;133(7):2098-114.

16.

Volkow ND. What Are Hallucinogens and Dissociative Drugs? NIDA

Research Report Series 2015;5:1-8.

17.

Carhart-harris RL, Erritzoe D, Williams T, Stone JM, Reed LJ, Colasanti A, et

al. Neural correlates of the psychedelic state as determined by fMRI
studies with psilocybin. Proc Natl Acad Sci U S A 2012 Feb 7;109(6):2138-43.

18.

Narang R, Jadun CK, Carr B. A case of MDMA toxicity with unusual clinical
and neuroradiological features. Journal of Intensive Care Society
2014;15(1):70-73.

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FOR YOUR ATTENTION