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
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
64
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
7
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
8
‘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________
9
Must go beyond associations to predictions
Apud et al. Neuropsychopharm 2007
25
27
29
31
33
35
Placebo Tolcapone
V/V (n=14)
M/M (n=7)
Num
ber
of w
ords
Verbal memory trials 1–3
10
‘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
•13
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
14
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
•15
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
•16
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
-3
-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
•15
•10
•5
•0
•15
•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
31
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
32
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