FUNCTIONAL CONNECTIVITY AS A BIOMARKER FOR TREATMENT RESPONSE IN SCHIZOPHRENIA Jennifer Hadley1,2, Rodolphe Nenert3, David White1, Kristina M. Visscher3, and Adrienne C. Lahti1

1Neuroimaging and Translational Research Lab, Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham 2Medical Scientist Training Program; Department of Biomedical Engineering, University of Alabama at Birmingham 3Department of Neurobiology, University of Alabama at Birmingham

R E F E R E N C E S 1: Creese, I., D. R. Burt and S. H. Snyder (1976). "Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs." Science

192(4238): 481-483. 2: Seeman, P. (1987). "Dopamine receptors and the dopamine hypothesis of schizophrenia." Synapse 1(2): 133-152. 3: Kapur, S., R. Zipursky, C. Jones, G. Remington and S. Houle (2000). "Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind

PET study of first-episode schizophrenia." Am J Psychiatry 157(4): 514-520. 4: Harrow, M., J. R. Sands, M. L. Silverstein and J. F. Goldberg (1997). "Course and outcome for schizophrenia versus other psychotic patients: a longitudinal study."

Schizophr Bull 23(2): 287-303. 5: Arranz, M. J. and J. C. Munro (2011). "Toward understanding genetic risk for differential antipsychotic response in individuals with schizophrenia." Expert Rev Clin

Pharmacol 4(3): 389-405. 6: Buchanan, R. W. and W. T. Carpenter (2000). Schizophrenia: Introduction and Overview. Comprehensive Textbook of Psychiatry. B. J. Sadock and V. A. Sadock.

Philadelphia, Pennsylvania, Lippincott, Williams, and Wilkins: 1096-1110.

D I F F E R E N C E S I N V T A F U N C T I O N A L C O N N E C T I V I T Y

SCHIZOPHRENIA is a severe , l i fe long mental illness that often leads to profound disabi l i ty. Physicians treat schizophrenia using antipsychotic drugs (APDs), which generally act as antagonists on the dopaminergic D2 receptors1,2,3. Patient responses to these drugs are variable and currently unpredictable4,5,6, presenting a significant challenge to physicians.

Widespread evidence supports the role of dopamine in patient response to APDs. Notably, dopaminergic neurons originating in the ventral tegmental area (VTA) project to many regions that show changes in blood flow after APD treatment7.

BASED ON THIS INFORMATION, WE HYPOTHESIZED THAT: •  T H E R E A R E S P E C I F I C D E F I C I T S I N F C I N

UNMEDICATED SCHIZOPHRENIA •  THESE DEFICITS ARE AFFECTED BY APD TREATMENT •  VTA FC TO ONE OR MORE REGIONS OF THE BRAIN CAN

PREDICT PATIENT RESPONSE TO APDS.

FRONTAL CORTEX

LIMBIC CORTEX Thalamus

HIP

NAc

VTA

D o p a m i n e

G l u t a m a t e

G A B A

Projections of the mesocorticolimbic dopamine system. These regions are also connected by other neurotransmitters i m p l i c a t e d i n t h e p a t h o l o g y o f schizophrenia, shown below.

D O P A M I N E P R O J E C T I O N S

F U N C T I O N A L C O N N E C T I V I T Y

time

BO

LD fM

RI

sign

al

Functional connectivity (FC) is a measure of the synchrony of spontaneous neural activity9. It reflects pathologically relevant underlying neuronal circuitry10, a n d i s k n o w n t o b e a l t e r e d i n schizophrenia11, 12, 13, 14, and may be a biomarker for treatment response.

FC = ρ =cov Χ,ϒ( )σ Χσ ϒ

Ba

ckg

rou

nd

EPI Data

• Slice timing correction • Reslice to 2mm3

• 3D motion correction • Coregister to structural scan • Spatially smooth and normalize to MNI space

• Nuisance regression using movement parameters • Identify bad scans using FD and DVARS • Interpolate bad scans • Band-pass filter: • Temporally mask bad scans • Extract WM and CSF components • Nuisance regression using WM and CSF components

0.009 ≤ f ≤ 0.08

Functional Connectivity Group

Differences

(SPM

8)

(Cus

tom

)

• Extract 1st eigenvariate of BOLD signal from regions of interest

• Correlate extracted time series with those from whole brain, voxel-wise to make functional connectivity maps.

• Compare functional connectivity maps between participant groups to assess group differences. SE

ED-B

ASE

D

CO

RR

ELAT

ION

Preprocessed Data

PREP

RO

CES

SIN

G

D A T A A N A L Y S I S

S T U D Y D E S I G N

Met

hod

s

Res

ult

s

V T A F U N C T I O N A L C O N N E C T I V I T Y P R E D I C T S T R E A T M E N T R E S P O N S E

Con

clu

sion

s

Baseline   1   6  2   5  4  3  

✓   ✓   ✓   ✓   ✓   ✓   ✓  

0 5

MCC

PrC, PoC

PC

SMC

MCC

SMC

C. Thalamus rsFC: SZ0 < SZ1 B. VTA rsFC: SZ0 < SZ1

Thal

Thal

Thal

7.5, -13.5, 3 -13.5, -19.5, 3

ACC, MCC

Thal

Thal

MCC

SFG

MTG

In

FG

PC, MTG

FG

In

MOG

Thal

A. VTA rsFC: HC > SZ0

9, -4.5, 3

E. VTA rsFC: HC < SZ1

30.5, -13.5, 3

SMC

ACC

MCC

SFG

PC, PCC

MFG

MFG

D. VTA rsFC: HC > SZ1

7.5, -13.5, 15

MTG

STG

FG

A. VTA rsFC in SZ0 correlated with better TR 0 5

Dorsal anterior cingulate cortex

-13.5

B. VTA rsFC in SZ0 correlated with worse TR

-6

VTA to medial prefrontal cortex VTA to precuneus

1 2 3 4 5 6

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

rsFC Strength

TR

R² = 0.171

6 1 2 3 4 5

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

rsFC Strength

TR

R² = 0.1585

6 1 2 3 4 5

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

rsFC Strength

TR

R² = 0.4888

VTA to dorsal anterior cingulate cortex

Medial prefrontal cortex

Posterior cingulate cortex / precuneus

Lateral parietal cortex

Posterior cingulate cortex / precuneus

Medial prefrontal cortex

30

1. T h e r e i s a s i g n i f i c a n t d e c r e a s e i n V T A F C i n u n m e d i c a t e d s c h i z o p h r e n i a c o m p a r e d t o m a t c h e d h e a l t h y c o n t r o l s . While this is the first study to look at VTA FC, previous studies have reported decreased FC to these regions in schizophrenia8. Other studies report reduced thalamic metabolism9 and decreased dopaminergic projections to the thalamus in schizophrenia10, as well as abnormalities in the intracellular integration of dopamine with other neurotransmitter systems11.

2. A P D t r e a t m e n t r e v e r s e s s o m e , b u t n o t a l l , V TA F C d e f i c i t s . VTA to thalamus FC was restored following one week of APD treatment; other regions showed no change in VTA FC. APDs act on the dopaminergic D2 receptor, which is thought to inhibit activity of the indirect pathway of the basal ganglia12,13. This would lead to decreased inhibition of the thalamus by the VTA in unmedicated schizophrenia, which would be corrected with APDs. Thalamic FC to the regions with remaining VTA FC deficits was restored with treatment.

3. V TA F C t o t h e d A C C i s p o s i t i v e l y c o r r e l a t e d w i t h t r e a t m e n t r e s p o n s e ; V TA F C t o t h e D M N i s n e g a t i v e l y c o r r e l a t e d w i t h t r e a t m e n t r e s p o n s e . Previous studies have predicted APD response before initiating treatment14,15, and found it to depend on dopamine release15. It was also reported that FC of the DMN increased with an acute dose of L-dopa and decreased with an acute dose of haloperidol (both change dopamine levels)16.

7: Lahti, A. C., M. A. Weiler, H. H. Holcomb, C. A. Tamminga and K. L. Cropsey (2009). "Modulation of limbic circuitry predicts treatment response to antipsychotic medication: a functional imaging study in schizophrenia." Neuropsychopharmacology 34(13): 2675-2690.

8: Zhou, Y., M. Liang, L. Tian, K. Wang, Y. Hao, H. Liu, Z. Liu and T. Jiang (2007). "Functional disintegration in paranoid schizophrenia using resting-state fMRI." Schizophr Res 97(1-3): 194-205.

9: Holcomb, et al. (1996) “Functional sites of neuroleptic drug action in the human brain: PET/FDG studies…” American Journal of Psychiatry 10. Clinton , et al. (2005) “Dopaminergic Abnormalities in Select Thalamic Nuclei in Schizophrenia …” American Journal of Psychiatry 12: Gerfen, C. R. (2000). "Molecular effects of dopamine on striatal-projection pathways." Trends Neurosci 23(10 Suppl): S64-70. 13: Gerfen, C. R., J. F. McGinty and W. S. Young, 3rd (1991). "Dopamine differentially regulates dynorphin, substance P, and enkephalin expression in

striatal neurons: in situ hybridization histochemical analysis." J Neurosci 11(4): 1016-1031. 14: Buchsbaum, M. S., S. G. Potkin, B. V. Siegel, Jr., J. Lohr, M. Katz, L. A. Gottschalk, B. Gulasekaram, J. F. Marshall, S. Lottenberg, C. Y. Teng and et al.

(1992). "Striatal metabolic rate and clinical response to neuroleptics in schizophrenia." Arch Gen Psychiatry 49(12): 966-974. 15: Abi-Dargham, et al. (2000). “Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.” Proc Nat Acad Sci USA. 94(14):8104-9 16: Cole, et al. (2012) “Dopamine-dependant architecture of cortico-subcortial network connectivity.” Cerebral Cortex.

A C K N O W L E D G M E N T S A N D F I N A N C I A L D I S C L O S U R E S

Support for this work was provided by the National Institutes of Health (R01MH081014) to A.C.L. and by the University of Alabama at Birmingham Medical Scientist Training Program to J.A.H.