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Neural substrate for mental illnessTung-Ping Su
Department of PsychiatryNational Yang-Ming University
Taipei Veterans General Hospital
Nov.14, 2006 at Brain Institute, NYMC
Dopaminergic pathway
Noradrenergic pathway
Serotonergic pathway
精神疾病之主要分類精神疾病之主要分類精神疾病
重型疾病 輕型疾病
精神分裂症情感性精神症 身體化症
泛焦慮症
創傷後症候群
強迫症
社交畏懼症
恐慌症
輕鬱症躁
鬱症
重鬱症
老人失智症與
其他精神疾病
兒童青少年
精神疾病
人格疾患
器質性腦症候群
藥物、酒精濫用
Pathogenesis: worry and anxiety
Culpepper explained: anxiety expressed through high cortical activity, which can be activated by sudden noise or memories---stimulate other portions of brain --- SxsJ Clin Psychiat 2004
Chrousos JAMA 1992Chrousos JAMA 1992
The Brain Circuits of GAD:Overactive fronto-cortical-basal gangalial loop
David J Nutt2000
• OCD:OrbitofrontalFC -- BG• GAD:Rostral partsFC --BG
Integrating neurochemistry and brain circuits of GAD
D J Nutt2000
Neuroimaging studies in GNeuroimaging studies in GADAD
Benzodiazepine Benzodiazepine receptorsreceptors in in GADGAD
Controls(grand average)
GAD patients(grand average)
Decreased BDZ receptor binding of [123I]NNC 13-8241 in left temporal pole ofGAD patients indicates less homogeneous receptor density distribution
Tiihonen et al, 1997
Neuroimaging of
Panic Disorder
Neuroanatomy of Panic DisorderImplication of functional imaging in fear conditioning
Pathway of viscerosensory information in the brainPathway of viscerosensory information in the brain
BP, HRvia NE release
Respiratory rate
cortisol
PAG: defensive B,Pain modulation
Contextual & cueFear conditioning
Memory processing Direct mode
Fast circuit
Indirect modeSlow circuit
Neurocircuitry of PD
Fast mode bottom-up
Slow mode, top-down
Efferent pathways from amygdalato elicit autonomic symptoms and neuroendocrino
logy
PAGPAG LCLC
PBNPBNHPA axisHPA axis
Hypothalamus
pituitary
Amygdala
Hippocampus
Temporal lobe
T1 weighted imageT1 weighted image
Amygdalar atrophy in panic disorder patients (VMRI) Massana G et al.: NeuroImage 19 (2003) 80–90
SmallerLt 23.4%Rt 31.9%
PD vs. CRL
NS for bothsides
NS for bothsides
Voxel-based morphometry of gray matter utilizing Jacobian modulation: 10 panic disorder patients versus 23 normal controls p < 0.001) (right=right, left=left),
• Increased gray matter vol. in the dorsal and ventral midbrain and rostral pons of the brainstem. (bottom-up)
• Increased left ventral hippocampal, right occipital and right middle temporal volumes.
• Decreased regional prefrontal cortex volumes (top-down)
Protopopescu X et al, Neuroreport, 2003
5-HTT binding in the midbrain of a control subject (A) and a patient with current PD (B). 5-HTT—serotonin transporter, PD—panic disorder Maron E et al 2004, Psychiatric research neuroimaging;132:173-181
Reduced brain 5-HTT binding in patients with panic disorder
• Decrease in 5-HTT binding in the midbrain, temporal lobes and thalamus vs. the control.
• The PD in remission was similar to CRL in the midbrain and in the temporal lobes, but lower in the thalamus (trait marker)(trait marker) (5-HTT binding).
• Regional 5-HTT binding negatively correlated with the severity of panic symptoms.
Remission is with normalization of 5-HTT binding.
• Deficit in brain 5-HT ---panic or reflect a compensatory Process in 5-HT system?
Middle brain (12 mm above the anterior commisure–posterior commisure plane) median volume of distribution map for controls (left) and patients with panic disorder (right). Note the generalized decreasedecrease in volume of distribution affecting the thalamithalami and the heads of the caudate nucleuscaudate nucleus. PD may be due to defective brain inhibition--- allow paroxysmal elevations of anxiety during panic attacks.
Decreased brain GABAA-Benzodiazepine receptor binding by C11flumazenil in PD, Malizia AL et al.: Arch Gen Psychiatry 55(1998) 715–720
Orbito-frontal
Insula
thalamus
Caudate
China TaipeiSARS,2003
Kao-ShungSARS, 2003
Nan-TouEpicenter of 921 EQ 1999
Su, 2005
Symptoms of PTSD
Overwhelming trauma
1. Reexperience of traumatic
events (flashback)
2. Startling response
3. Avoidance
Results and Discussion
Emotional Stroop Task
PTSD, p<0.01
Results and Discussion
Classical Conditioning for PTSD
Patient, p<0.05
1H-MR spectrum from human brain1H-MR spectrum from human brain
1652718-7 Tsai
0.95
1.08
2001 2003
1.22
NAACho Cr Cho Cr
NAA
1.17Cho Cr
NAA
NAA
CrCho
0.8
1
1.2
1.4
1.6
1.8
2
NAA
/ Cr
0.8
1
1.2
1.4
1.6
1.8
2
NA
A /
Cr
Comparison of NAA/Cr ratio of bilateral hippocampus Comparison of NAA/Cr ratio of bilateral hippocampus PTSD (n = 11) vs. Taipei controls (n = 13) in 2001PTSD (n = 11) vs. Taipei controls (n = 13) in 2001
Left hippocampus Right hippocampus
*
TPE-CTL TPE-CTL PTSD PTSD
(*: P<0.05 )
Response to stress in normal, major depression and PTSD
Hypothesis for disaster-related PTSD
Overwhelming stress
HPA axis
• Memory, attention and emotion impairment: Lower NAA/Cr (Lt. hippocampus) Poorer neurocognitive function Low basal cortisol
DST dysregulation
Affective DisordersAffective Disorders
Tung-Ping Tom Su, MDTung-Ping Tom Su, MD
Department of PsychiatryDepartment of Psychiatry
Veterans General Hospital-TaipeiVeterans General Hospital-Taipei
National Yang-Ming UniversityNational Yang-Ming University
Cerebral glucose metabolism: PET study
A Little Science FictionA Little Science Fiction
Atrophic“depressed”
“Treated”
PET–Impaired PerfusionPET–Impaired Perfusion
Drevets WC, et al. Nature. 1997;386(6627):824-827.
X=-3
Y=31
Subgenual PFC
-5.5 -2.5 0I-Value
fMRI responses in patients with depression
• Caudate activation as a correlate of intrinsic learning
• Reduced activation in older patients with depression
• Future of psychological probes and fMRI in patients with post-infective fatigue states
4.8
5
5.2
5.4
5.6
5.8
6
6.2
6.4
6.6
Control Early Onset Late Onset
Aetiological Group
Hipp
ocam
pal V
olum
e (m
m3)
Depression: imaging finding
Depression: 1. increase BF/GMR of medical orbital , VMPFCor amygdala, or pregenual ant. Cingulate2. Decrease DLPFC and subgenual portion of ant. cingulate
Frontal-subcortical circuit
governance
• Lt frontal: positive emotion
• Rt frontal: negative emotion
Acute depression (transient sadness)Lt PFC activity increase
Chronic depressionLt PFC activity decrease
• Similar to seizure:
Cingulate:Attention& mood
Amygdala:Emotional recognition of facesLt Amygdala activated during sadness
• Personality change
New Concept of Treatment New Concept of Treatment in Psychiatric Disorders: in Psychiatric Disorders:
• TMSTMS
• VNSVNS
• DBSDBS
Repetitive Transcranial Repetitive Transcranial Stimulation (rTMS)Stimulation (rTMS)
Time-varying electrical current in a coil produces
Focal 2 tesla magnetic field
Passes unimpeded through skull induces current in neurons
Behavioral change
• ResultsResults
Hamilton Depressive Rating Scale
0
5
10
15
20
25
30
35
40
Baseline 1st week 2nd week 3rd week 4th week
Time
Open Trial of rTMS, Huang & Su: European Psychiatry 19 (2004) 523-524
躁鬱症
雙極性情感性障礙
高潮
低潮
The dopamine system
Stahl SM. Psychopharmacology of Antipsychotics. 1st ed. 1999.
Developmental dysregulation of the dopamine sysDevelopmental dysregulation of the dopamine system and the pathophysiology of schizophreniatem and the pathophysiology of schizophrenia
Prefrontal cortex
Amyg-dala
HypothalamusHPA axis
Ventralhippocampus
LC
StressStress1.1. Genetic: diffuse subtle Genetic: diffuse subtle
changes in PFCchanges in PFC
suppressionsuppression
VTAVTA
DA: hyper-activatedto stress
SCZ: pathology in cortico-limbic circuit:2. abnormal striatal DA2. abnormal striatal DA
•Delayed onset ofSCZ: delayed delayed pathology (damage)pathology (damage) in hippocampusin hippocampus(interaction of (interaction of stress vs. stress vs. hippocampus basedhippocampus basedon PFC disruptionon PFC disruption))
Mesocorticalpathway
Su TP, 2005Su TP, 2005
Increased release of glucocorticoids under stress
damagedamage
In-vivo Mapping of Fiber Pathways in
Schizophrenia
Using Diffusion Tensor MRI
Tung-Ping Su, MD, Yuan – Hwa Chou, MD, PhD Ya-Mei Bai, MD, PhD, Kun-Hsien Chou, Fang-Ying Chiu, Chin-Po Lin, PhD
Brain Function and Imaging LaboratoryDepartment of Psychiatry, TVGH & NYMUInstitute of Neuroscience, NYMU
x
Water diffusion behavior
• Diffusion Weight Image (DWI)
• Diffusion Tensor Imaging
• Q-ball, DSI
Image Lab and Brain connectivity Lab, NYMU, Taiwan
Diffusion Tensor Imaging (DTI)
Basser et al. (Biophys J 1994)
Dxx Dxy Dxz
Dyx Dyy Dyz
Dzx Dzy Dzz
x
y
z
x
y
z
xx
yy
zz
yz
xy
xz
1st eigenvector field
Normalize
13
12
11
1
13
12
11
E
E
E
E
E
E
DzzDzyDzx
DyzDyyDyz
DxzDxyDxx
Tractography – FACT algorithm
Image Lab and Brain connectivity Lab, NYMU, Taiwan
Short arrows represent vector directions of the largest principal axis.
A tracking (a long arrow) is started from a center of a selected voxel and
a line is propagated by observing the vector direction of each voxel
( Fiber Assignment by Continuous Tracking )
Normal control > Schizophrenia subjects
Cluster size
Coordinates of the most significant voxel T-score Anatomical location
Voxels x y z R/L 984 -6 6 20 4.93 L Corpus callosum424 42 -2 24 4.44 R Frontal sub-gyral WM175 32 -66 18 3.93 R Middle temporal gyrus WM
92 30 20 20 3.54 R Frontal sub-gyral WM
89 32 42 2 3.49 R Frontal sub-gyral WM72 12 -24 -22 3.16 R Brain stem
60 -36 0 38 2.97 L Middle frontal WM, BA 6
49 20 -32 28 3.16 R Corpus callosumStatistical criteria: p-value < 0.01, cluster > 48 voxels
Normal volunteers : 36 healthy subjects, 23 F and 13 M, 42.73 ± 11.19 y/oSchizophrenia : 18 patients, 12 F and 6 M, 41.36 ± 9.64 y/o
Schizophrenia Study
Normal > Schizophrenia subjects
Result (I) : Compare Normal Volunteers to Schizophrenia
偵測過動兒症及雙極性情感症疾患之腦部白質的異常
擴散張量造影(Diffusion Tensor Imaging)
Decreased FA values of the brain areas
in the comparison among controls, bipolar & unipolar
Normal > BD
MDD > BD
Ventral
Ventralstriatum
Orbitofrontalcortex
Thalamus(MD)
AnteriorCingulate(SGPFC)
Expression of BipolarDisorder
Amygdala
Cerebellarvermis
Hypothalamua
‘Cognitive’ cortical areas(e.g., DLPFC)
A BAnterior limbic network
JoBuat 6 months old
1 yrs old
1 yrs old
16 months old
Thanks for your attention !