Use of Functional Brain Circuitry for Diagnostic and Treatment Decisions

Steven G. Potkin, MD Professor Brain Imaging Center

Robert R. Sprague Endowed Chair in Brain Imaging UC Irvine

February 20, 2013

Goal to Improve Diagnosis & Treatment Predictions

DSM IV & V based on symptom constellations that may not sufficiently distinguish biological

homogenous groups and corresponding treatment response

Functional Brain Circuitry May be Closer to Underlying Etiology than Symptoms

• Current diagnostic system based on subjective patient reports may be inadequate to distinguish meaningful biological differences and subtypes

• Quantitative changes in brain circuitry often predate or precede clinical changes, and thus, can be important in early diagnosis and prediction of treatment response

• Maybe meaningful final common pathways as limited number of brain systems producing behaviors e.g. hallucinations use same auditory system

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Outline

o Prefrontal Cortical Pyramidal Neuron and Its Connections

• Dopamine-related COMT & DRD1

o Cholinergic System Projections and Their Relationship to

Attention & Memory Across Disorders

o Implications for drug development & intervention

Convergence onto the final common pathway on the PFC pyramidal neuron..and its loops

Fallon, Opolo, Potkin, 2003

Dopamine terminals in striatum and in prefrontal cortex are not the same

Modified after: Sesack et al 1998 Weinberger,

2003, Lanzenberger, 2011

Striatum

Prefrontal cortex

DA

DA transporter

DA receptor

COMT

NE transporter

•DA transporter distribution

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PFC Brain Inefficiency & Effect of COMT genotype

Egan et al PNAS 2001

vv>vm>mm, SPM 99, p<.005

Physiological efficiency

fMRI

‘vv’ - high COMT activity LOW synaptic dopamine

‘vm’ – intermediate

‘mm’ – low activity HIGH synaptic dopamine

Working memory PFC Activation

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‘vv’ - high COMT activity LOW synaptic dopamine

Arnsten and Goldman-Rakic, 1986 Arnsten et al., 1994 Murphy et al., 1994, 1996 a,b, 1997 Williams and Goldman-Rakic, 1995 Verma and Moghaddam, 1996

‘mm’ – low activity HIGH synaptic dopamine

Predicted relative effects of COMT genotype on prefrontal cortical function

______Optimal________

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Must go beyond associations to predictions

Apud et al. Neuropsychopharm 2007

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Placebo Tolcapone

V/V (n=14)

M/M (n=7)

Num

ber

of w

ords

Verbal memory trials 1–3

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‘vv’ - high COMT activity LOW synaptic dopamine

Arnsten and Goldman-Rakic, 1986 Arnsten et al., 1994 Murphy et al., 1994, 1996 a,b, 1997 Williams and Goldman-Rakic, 1995 Verma and Moghaddam, 1996

‘mm’ – low activity HIGH synaptic dopamine

Predict that DRD1 genotype will influence prefrontal cortical function

______Optimal________

3’ 5’ Exon

-94 G/A 5’UTR BstNI

-48 A/G 5’UTR DdeI

+1263 G/A PvuI

+1403 T/C 3’UTR Bsp1286I

DRD1 Polymorphisms

D1 receptor most prevalent dopamine receptors in human cortex Putative regulatory region of DRD1

Allele 1 (A) is more common (~65% in our Caucasian sample & ~90% in our African American sample) than allele 2 (G)

DRD1 Genotypes can predict clinical response to medication: e.g. clozapine

AA Genotype 28% Improvement GG and GA 7% worse

From: Potkin et al 2003

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Trails B Performance by DRD1 Genotype C-MINDS Battery

Trails B (time to complete a task of connecting alternating numbered and lettered circles in order) – p < .011

Could Trails B predict clozapine response as well

as FDG PET imaging?

Depends on ROC curves

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DRD1 Polymorphisms in Clozapine Response (N=234)

4) rs265976 A/C

3) +1403 A/G 2) -48 A/G 1) -800 T/C

3 2 1

Prom

1 Prom

2

Coding Region

Ethnicity Global P Value

Haplotype Responder: n (Est. Freq.)

Non-Responder: n (Est. Freq.)

P Value

Caucasian 0.616 1-2-1-2 0.9 (0.01) <5.7 (0.02) 0.016

African-American 0.189 1-2-2-2 3.0 (0.06) >0.0 (0.00) 0.042

-48 G allele over represented in the non responders “2” is the G allele; molecular mechanism unknown

Hwang R et al ASSOCIATION STUDY OF FOUR DOPAMINE D1 RECEPTOR GENE POLYMORPHISMS AND CLOZAPINE TREATMENT RESPONSE, 2007

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Functional Connectivity • Spontaneous low-frequency fluctuations in BOLD-weighted MRI data

are correlated between brain regions known to be involved in similar task performance:

• Related to the Local Field Potentials (LFP) and gamma band power • Easy to get with 6 minutes MRI scan cf’d to task based fMRI

– Motor system: Biswal et al. 1995, Lowe et al. 1998, Gao et al., 1999

– Visual system: Lowe et al. 1998, Cordes et al. 2001,Hampson et al. 2004

– Auditory system: Cordes et al., 2001

– Cognitive systems: Lowe et al. 2000, Hampson et al. 2002

Vince D. Calhoun, HBM 2009

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Default Mode Components for BP, SZ, and HC

V. D. Calhoun, G. D. Pearlson, P. Maciejewski, and K. A. Kiehl, "Temporal Lobe and 'Default' Hemodynamic Brain Modes Discriminate Between Schizophrenia and Bipolar Disorder," Hum. Brain Map., In Press.

Analysis of Resting State: eyes-closed resting state fMRI scans

• Voxelwise measures of the amplitude of low frequency fluctuations (ALFF) and fractional ALFF (fALFF) in resting state fMRI – correction for white matter, CSF signals, motion

– schizophrenia show greater low frequency power in the frontal cortex, and less

in posterior lobes than do healthy participants.

HC > SZ, t > 2.7 SZ > HC, t > 2.5

Analysis of Resting State: eyes-closed resting state fMRI scans

• Seed based activation time series analyses – correlation between seeds and every voxel or target – medial geniculate nucleus relay connections to auditory cortex

– medial dorsal nucleus with its higher order connections with PFC.

– two cortical ROIs: frontal (ACC) and temporal (STG) cortex.

Medial Dorsal Nucleus Connectivity: HC vs. SZ (p<.025), k=100

Medial Geniculate Nucleus Connectivity: HC vs. SZ (p<.025), k=100

Regardless of whether connectivity was calculated with MDN or MGN, patients showed greater connectivity with the temporal lobe than did controls and controls showed greater connectivity with medial frontal cortex than patients. fBIRN analysis Judy Ford 2013

Activity in the right superior temporal gyrus (Wernicke’s area homologue) is correlated with activity left putamen in schizophrenia patients who hear voices commenting and not in normals

Ford et al 2012 R Wernicke seed

Resting State fMRI Functional Connectivity & Hallucinations

L Putamen

Can pharmacological intervention alter connectivity? Can connectivity predict pharmacological response?

• Several studies have shown that the pattern of cognitive impairment can be distinguished between individuals with AD and SCZ.

• Identification of commonalities, however, may prove far more informative for our purposes.

SCZ & AD: Differential Cognitive Profiles?

3.5

-3

2.5

-2

1.5

-1

0.5

0 SCZ AD SCZ AD SCZ AD SCZ AD SCZ AD SCZ AD SCZ AD SCZ AD SCZ AD SCZ AD

Immediate Recall Delayed Recall Category Fluency Letter Fluency Symbol-Digit Trails A Trails B Letter Number Finger Tapping

(Dominant) Finger Tapping (NonDominant)

Word List Memory Language Attention Executive Motor

Z-Score Comparisons on Traditional Neuropsychological Tests: 150 schizophrenia (n=150) with mild-to-moderate AD (n=120).

•*3-Trial AVLT for SCZ and 3-Trial ADAS-Cog for AD; both scaled to respective norms for each measure.

Z-Score Comparisons on Subscales and Total Score on the MoCA

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-2.5

-2

-1.5

-1

-0.5

0 SCZ MCI AD SCZ MCI AD SCZ MCI AD SCZ MCI AD SCZ MCI AD SCZ MCI AD SCZ MCI AD SCZ MCI AD

Executive* Naming Attention* Language* Abstraction* Recall* Orientation MoCA* Total

Commonalities in Neuropathology?

• Many of the same brain areas ultimately involved but very different trajectory and different pathology

• Or maybe not?

Trajectories of Cholinergic Pathways

•C

•P •GP

•IN

•SF

•C‡S •iNC

•Nbm-Ch4

•P

•AvN •E

w

•H

•Selden NR, Gitelman DR, Salamon-Murayama N, et al. Brain. 1998(Dec);121(pt 12):2249-2257

Rivastigmine (n=10) vs. Placebo (n=13) in SCZ (covaried for BL differences)

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

Baseline Month2 Month4

Composite CMINDS Total Score

Exelon

Placebo

Composite CMINDS Computer Total Score

Wisc Card Sort Task RCT of Rivastigmine Augmentation

in Schizophrenia

112114116118120122124126

csttrls csttrls2 csttrls4

Exelon

Placebo

00.5

11.5

22.5

3

cstcat cstcat2 cstcat4

Exelon

Placebo

•Trials to complete •Categories completed

Rivastigmine (n=10) vs. Placebo (n=13) in SCZ Neurocognitive

Domain Tx Baseline z-score

EOS z-score

Percent Improvement

BL-Covaried GLM F-value p-value

Memory Rivastigmine -0.78 -0.57 27% 1.863 0.187

Placebo -1.14 -1.21 -6%

Attention Rivastigmine -0.76 -0.51 33% 4.168 0.055

Placebo -1.56 -1.54 1%

Executive Rivastigmine -1.24 -0.75 40% 9.767 0.005

Placebo -1.30 -1.55 -19%

Language Rivastigmine -0.19 -0.07 63% 0.387 0.541

Placebo -0.73 -0.60 18%

Motor Rivastigmine -0.73 -0.53 27% 1.734 0.203

Placebo -0.89 -1.02 -15%

Overall Rivastigmine -0.74 -0.47 36% 8.156 0.010

Placebo -1.12 -1.18 -5%

Decreased Cholinergic Activity Associated with Neuropathology of AD, DLB, PD

Perry et al., 1985, 1994

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•10

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•0

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•10

•5

•0

•4

•3

•2

•1

•0 NC AD DLB PD NC AD DLB PD NC AD DLB PD

Parietal cortex

Temporal cortex

Occipital cortex

Pontine ChAT is decreased 46 to 76% in SCZ and correlated with orientation and reasoning (Karson et al 1993, 1996)

& perhaps SCZ

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Functional Brain Circuitry

Two circuits: PFC working memory (COMT & DRD1) & cholinergic attention cognition circuit

Dopamine-related working memory is modifiable by a predictable pharmacological manipulation

Cholinergic augmentation may be general cognitive enhancer independent of cause of dysfunction or dx

Collecting data across traditional diagnostic categories will produce surprises; both positive and negative

Reminder that causality, course and treatment response factors may be distinct from one another

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Implications for Diagnostic Categories for the Schizophrenias

Inadequate information on dimensionality

Great need for empirical data with both approaches in same group to validate both approaches

Dimensions extend into normal populations and thus raise questions of cognitive enhancement for these normals