Use of Functional Brain Circuitry for Diagnostic and Treatment Decisions

Transcription

1 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

2 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

3 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

4 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

5 Fallon, Opolo, Potkin, 2003 Convergence onto the final common pathway on the PFC pyramidal neuron..and its loops

6 Dopamine terminals in striatum and in prefrontal cortex are not the same Striatum DA DA transporter DA receptor COMT NE transporter Prefrontal cortex DA transporter distribution Modified after: Sesack et al 1998 Weinberger, 2003, Lanzenberger, 2011

7 PFC Brain Inefficiency & Effect of COMT genotype Working memory PFC Activation Physiological efficiency fmri vv - high COMT activity LOW synaptic dopamine vv>vm>mm, SPM 99, p<.005 mm low activity HIGH synaptic dopamine vm intermediate Egan et al PNAS

8 Predicted relative effects of COMT genotype on prefrontal cortical function Optimal 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 vv - high COMT activity LOW synaptic dopamine mm low activity HIGH synaptic dopamine 8

9 Must go beyond associations to predictions Verbal memory trials 1 3 Number of words Placebo Tolcapone V/V (n=14) M/M (n=7) Apud et al. Neuropsychopharm

10 Predict that DRD1 genotype will influence prefrontal cortical function Optimal 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 vv - high COMT activity LOW synaptic dopamine mm low activity HIGH synaptic dopamine 10

11 DRD1 Polymorphisms 5 Exon 3-94 G/A 5 UTR BstNI -48 A/G 5 UTR DdeI G/A PvuI T/C 3 UTR Bsp1286I 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)

12 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 13

14 DRD1 Polymorphisms in Clozapine Response (N=234) 1) -800 T/C 2) -48 A/G 3) A/G Prom 1 Prom 2 Coding Region ) rs A/C Ethnicity Global P Value Haplotype Responder: n (Est. Freq.) Non-Responder: n (Est. Freq.) P Value Caucasian (0.01) <5.7 (0.02) African-American (0.06) >0.0 (0.00) 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,

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 Auditory system: Cordes et al., 2001 Cognitive systems: Lowe et al. 2000, Hampson et al Vince D. Calhoun, HBM 2009

16 Default Mode Components for BP, SZ, and HC 16 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.

17 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

18 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.

19 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

20 Resting State fmri Functional Connectivity & Hallucinations 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 L Putamen R Wernicke seed Ford et al 2012 Can pharmacological intervention alter connectivity? Can connectivity predict pharmacological response?

21 SCZ & AD: Differential Cognitive Profiles? 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.

22 Z-Score Comparisons on Traditional Neuropsychological Tests: 150 schizophrenia (n=150) with mild-to-moderate AD (n=120). Word List Memory Language Attention Executive Motor Immediate Recall Delayed Recall Category Fluency Letter Fluency Symbol-Digit Trails A Trails B Letter Number Finger Tapping (Dominant) Finger Tapping (NonDominant) 0 SCZ AD SCZ AD SCZ AD SCZ AD SCZ AD SCZ AD SCZ AD SCZ AD SCZ AD SCZ AD *3-Trial AVLT for SCZ and 3-Trial ADAS-Cog for AD; both scaled to respective norms for each measure.

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24 Z-Score Comparisons on Subscales and Total Score on the MoCA Executive* Naming Attention* Language* Abstraction* Recall* Orientation MoCA* Total 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

25 Commonalities in Neuropathology? Many of the same brain areas ultimately involved but very different trajectory and different pathology Or maybe not?

26 Trajectories of Cholinergic Pathways C S i NC C G P Nbm- Ch4 A E H vn w P I N S F Selden NR, Gitelman DR, Salamon-Murayama N, et al. Brain. 1998(Dec);121(pt 12):

27 Rivastigmine (n=10) vs. Placebo (n=13) in SCZ (covaried for BL differences) Baseline Month2 Month4 Composite CMINDS Total Score Exelon -0.8 Placebo Composite CMINDS Computer Total Score

28 Wisc Card Sort Task RCT of Rivastigmine Augmentation in Schizophrenia Trials to complete Categories completed csttrls csttrls2 csttrls4 Exelon Placebo cstcat cstcat2 cstcat4 Exelon Placebo

29 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 % Placebo % Attention Rivastigmine % Placebo % Executive Rivastigmine % Placebo % Language Rivastigmine % Placebo % Motor Rivastigmine % Placebo % Overall Rivastigmine % Placebo %

30 Decreased Cholinergic Activity Associated with Neuropathology of AD, DLB, PD & perhaps SCZ Parietal cortex 10 Temporal cortex 4 Occipital cortex NC AD DLB PD 0 0 NC AD DLB PD 0 NC AD DLB PD Pontine ChAT is decreased 46 to 76% in SCZ and correlated with orientation and reasoning (Karson et al 1993, 1996) Perry et al., 1985, 1994

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 31

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 32