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

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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 !