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D2/D3 dopamine receptor binding with [F-18]fallypride correlates of executive function in medication-naïve patients with schizophrenia
Nora S. Vyas
a,b,
, Monte S. Buchsbaum
c,d
, Douglas S. Lehrer
e
, Brian M. Merrill
e
, Alex DeCastro
c
,Nicholas A. Doninger
, Bradley T. Christian
g
, Jogeshwar Mukherjee
h
a
Kingston University London, Department of Psychology, Penrhyn Road, Kingston upon Thames, Surrey, KT1 2EE, UK 
b
Imperial College Healthcare NHS Trust, Charing Cross Hospital, Department of Nuclear Medicine, Fulham Palace Road, W6 8RF, UK 
c
University of California, San Diego, NeuroPET Center, Department of Psychiatry, 11388 Sorrento Valley Road, San Diego, CA, 92121, USA
d
University of California, San Diego, School of Medicine, Department of Radiology, 11388 Sorrento Valley Road, San Diego, CA, 92121, USA
e
Wright State University, Boonshoft School of Medicine, Department of Psychiatry, East Medical Plaza, Dayton, OH 45408, USA
Wright State University, Boonshoft School of Medicine, Department of Psychiatry, Wallace-Kettering Neuroscience Institute, Kettering, OH 45429, USA
g
University of Wisconsin-Madison, Waisman Laboratory for Brain Imaging and Behavior, Madison, WI 53705, USA
h
University of California, Irvine, Preclinical Imaging, Department of Radiological Sciences, CA 92697-5000, USA
a b s t r a c ta r t i c l e i n f o
 Article history:
Received 15 August 2016Received in revised form 10 May 2017Accepted 13 May 2017Available online xxxx
Convergingevidenceindicatesthattheprefrontalcortexiscriticallyinvolvedinexecutivecontrolandthatexec-utive dysfunction isimplicated inschizophrenia. Reduced dopamine D2/D3 receptor binding potentialhas beenreportedinschizophrenia, and the correlationswithneuropsychological testscores have beenpositive and neg-ative for different tasks. The aim of this study was to examine the relation between dopamine D2/D3 receptorlevels with frontal and temporal neurocognitive performance inschizophrenia. Resting-state
 18
F-fallypride pos-itron emission tomography was performed on 20 medication-naïve and 5 previously medicated for brief earlierperiods patients with schizophreniaand 19 age- and sex-matched healthy volunteers. Striatal and extra-striataldopamine D2/D3 receptor levels were quanti
󿬁
ed as binding potential using fallypride imaging. Magnetic reso-nance images in standard Talairach position and segmented into gray and white matter were co-registered tothe fallypride images, and the AFNI stereotaxic atlas was applied. Two neuropsychological tasks known to acti-vate frontal and temporal lobe function were chosen, speci
󿬁
cally the Wisconsin Card Sorting Test (WCST) andthe California Verbal Learning Test (CVLT). Images of the correlation coef 
󿬁
cient between fallypride binding andWCSTandCVLTperformanceshowedanegativecorrelationincontrasttopositivecorrelationsinhealthyvolun-teers.Theresultsofthisstudydemonstratethatlowerfallypridebindingpotentialinpatientswithschizophreniamay be associated with better performance. Our
󿬁
ndings are consistent with previous studies that failed to
󿬁
ndcognitive improvements with typical dopamine-blocking medications.© 2017 Elsevier B.V. All rights reserved.
Keywords:
CognitionCortexMemoryPositron emission tomographyPrefrontal cortex
1. Introduction
Neurocognitive impairments are a core feature of schizophrenia,with the largest effect sizes (
N
1.5 z-score differences) reported inboth executive function and verbal memory (Bilder et al., 2000;Dickinson and Harvey, 2009; Reichenberg et al., 2010; Vyas et al.,2012). Impairments in executive function are found to predict poorfunctionaloutcome,failureintreatmentinterventionsandlimitedreha-bilitation(Greenetal.,2000).Executivefunctionincludesmultiplecog-nitive constructs regulated by the coordination of multi-operationalneural systems and is a linchpin of cognitive ability (Bressler andMenon, 2010). It has been linked in functional neuroimaging studiesto the fronto-striatal-thalamic network thought to be associated withthe pervasive cognitive de
󿬁
cits reported in schizophrenia (Andreasen,1997; Andreasen et al., 1997; Buchsbaum et al., 1999; Hazlett et al.,2008; Kessler et al., 1993). This network, with its detailed neuroana-tomical structure (Alexander et al., 1986), is critical for performingtasks such as the Wisconsin Card Sorting Test (WCST) that are knownto elicit performance impairments in schizophrenia, and its dysfunc-tional operation demonstrated in unmedicated schizophrenia patientscon
󿬁
rmed with functional brain imaging approaches (see review andmeta-analysis, Buchsbaum et al., 2005). Abnormalities in the fronto-striatal-thalamic network have also been demonstrated in functionalmagneticresonanceimaging(fMRI)studiesofpsychosis-proneindivid-uals (Ettinger et al., 2013; Kumari et al., 2008).
 Corresponding author at: Kingston University London, Department of Psychology,Penrhyn Road, Kingston upon Thames, Surrey, KT1 2EE, UK.
E-mail address:
SCHRES-07307; No of Pages 15
http://dx.doi.org/10.1016/j.schres.2017.05.0170920-9964/© 2017 Elsevier B.V. All rights reserved.
Contents lists available at ScienceDirect
Schizophrenia Research
Pleasecitethisarticleas:Vyas,N.S.,etal.,D2/D3dopaminereceptorbindingwith[F-18]fallypridecorrelatesofexecutivefunctioninmedication-naïve patients with schizoph..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.05.017
 
Whilethestriatumandthalamusareknowntohavethehighestdo-pamine receptor concentrations in the brain, the frontal and temporallobes also contains signi
󿬁
cant numbers of receptors on rigorous post-mortemexamination( Joyceetal.,1991).High-af 
󿬁
nitydopaminerecep-tor ligands developed for positron emission tomography (PET) make itpossible to assess the fronto-striato-thalamic distribution of dopaminebinding. In healthy subjects signi
󿬁
cant extra-striatal binding has beendemonstrated (Buchsbaum et al., 2006; Farde et al., 1997; Lehrer et al.,2005; Mukherjee et al., 2002). In unmedicated and never-medicatedsubjectswithschizophrenia,abnormalitiesinextra-striataldopaminer-gic neurotransmission have been reported in the prefrontal cortex(Lehrer et al., 2010a) and the medial dorsal nucleus of the thalamus(Buchsbaum et al., 2006; Kessler et al., 2009; Lehrer et al., 2005;Suhara et al., 2002; Talvik et al., 2003; Yasuno et al., 2004). The earliestreport by Suhara and colleagues (Suhara et al., 2002) showed lowerbinding potential in the thalamus in patients with schizophrenia com-pared with controls (in retrospect, a one-tailed test would have been
 p
=0.03;seetheirTable1).Asinglephotonemissioncomputedtomog-raphy (SPECT) study using epidepride (Glenthoj et al., 2006) failed todetect binding reduction in the thalamus in patients with schizophre-nia, however this negative
 󿬁
nding may be due to lower resolution inSPECTimaging.Inourstudieswithhigher-resolutionPETthedecreasedbindinginschizophreniawasmostmarkedinthemedialdorsalnucleusisolated by tracingon co-registered MRI (Lehrer etal., 2010b),whereasin healthy subjects, the medial dorsal nucleus showed relatively higherbinding compared with other thalamic nuclei (Takahashi et al., 2006).Thereisincreasingevidencethatpatientswithschizophreniaexhibitimpairmenton executive function tasks,suchastheWCST and the Cal-ifornia Verbal Learning Test (CVLT), which is precisely aligned to non-motor fronto-striatal-thalamic circuits. Performance de
󿬁
cits in WCSTcategories achieved and perseverative errors has been widely docu-mented in
 󿬁
󿬁
citshavebeenfoundinschizo-phrenia (Bermanet al., 1995;Pateletal.,2010; Riehemannet al., 2001)andanactivationlikelihoodestimationmeta-analysisonaseriesoffMRIstudies using the WCST identi
󿬁
ed the frontal lobe, thalamus and stria-tumasimportantactivationsites(Buchsbaumetal.,2005).Theprevail-ing evidence from imaging studies suggests more widespread brainactivations during WCST performance (Barcelo et al., 1997; Nyhus andBarcelo, 2009). An EEG study of healthy individuals revealed increasedactivityduringtaskperformanceacrossallfrequencybandsinthefron-tal and temporo-parieto-occipital regions (except alpha), indicatingthat executive functioning skills underlying performance on the WCSTmay represent the operation of a more complex and widespread com-munication network (Gonzalez-Hernandez et al., 2002). Since dopa-mine projections are widespread, dopamine de
󿬁
cits may haveprofound effects on higher-order cognition (Vyas et al., 2011).The CVLT, a measure of verbal learning and memory that relies onserial-order and semantic-cluster strategies, also involves frontalareas, as demonstrated in patients with focal lesions (Alexander et al.,2003; Baldo et al., 2002), striatal activity in PET studies of normalaging (Brickman et al., 2003), and reduced functional connectivity be-tween the medial prefrontal, thalamus and striatum in fMRI studies of mild cognitive impairment (Liang et al., 2011). De
󿬁
cits in the CVLThave consistently been reported in early-onset (Brickman et al., 2004;McClellanetal.,2004;OieandRund,1999;Roofehetal.,2006),
󿬁
rst-ep-isode (Bilder et al., 2000; Hill et al., 2001; Saykin et al., 1994), chronic/ multiple-episode (Aleman et al., 1999; Heinrichs and Zakzanis, 1998)patients with schizophrenia, high risk studies (Hill et al., 2004;Paulsen et al., 1995), and a meta-analysis (Szoke et al., 2008). Four resting [F-18]fallypride PET studies in schizophrenia have re-ported low dopamine receptor binding potential in the medial dorsalnucleus of the thalamus (Buchsbaum et al., 2006; Kessler et al., 2009;Lehrer et al., 2010a; Yasuno et al., 2004), and in the prefrontal cortexin patients with schizophrenia (Lehrer et al., 2010a). A study using thehigh-af 
󿬁
nity radioligand [11C]FLB 457 PET also showed low D2/D3 re-ceptor binding in the right medial thalamus in drug-naïve patientswith schizophrenia compared with controls (Talvik et al., 2003).Since excess dopaminergic activity has been hypothesized to be in-volved in the pathophysiology of schizophrenia, we might expect thatpoorWCST performance would be associated witha more activedopa-mine system. In subjects with schizophrenia, higher
 18
F-FDOPA uptakehasbeenassociatedwithpoortaskperformanceontheWCSTpersever-ative errors (Meyer-Lindenberg et al., 2002). Another study showedthat more perseverative errors on the CANTAB Set shifting task weresigni
󿬁
cantly associated with lower binding potential in patients withschizophrenia (Fagerlund et al., 2013). Ghahremani and colleagues re-portedbetter(shorter)stop-signalreactiontimeassociatedwithhigherfallypride binding potential in the striatum (Ghahremani et al., 2012).Animalmodelshavedemonstratedthatthestriatumplaysanimpor-tant role in decision-making and performing goal-directed actions (Ito
 Table 1
Demographic characteristics and WCST performance in patients with schizophrenia and healthy volunteers.Parameter Schizophrenia (
n
 = 25) Healthy volunteers (
n
 = 19) StatisticAge, years 31.6 (12.2) 29.2 (9.2)
 
 =
0.73,
 df 
 = 42,
 p
 = 0.46Sex, M/F 18/7 12/7 Fisher's Exact test = 0.74Ethnicity, no. white/African American,African-Jamaican/African-Caribbean/Mixed16/0/1/1/1 22/3/0/0/0
 χ
2
= 6.24,
 p
 = 0.18Handedness, no. right/left-handed 23/2 16/3 Fisher's Exact test = 0.3WCSTCategories achieved 5.36 (1.34) 5.72 (0.95)
 
 = 0.21,
 df 
 = 34,
 p
 = 0.52Perseverative errors 14.78 (10) 11.72 (6.76)
 
 =
1.24,
 df 
 = 36,
 p
 = 0.22Shift learning 0.75 (0.06) 0.41 (0.71)
 
 =
1.1,
 df 
 = 35, p.27Total errors (
 score) 50.8 (11.83) 50.38 (10.98)
 
 =
0.11,
 df 
 = 36,
 p
 = 0.91CVLTTrials 1
5 43.4 (9.34) 54.68 (9.2)
 
 = 3.79,
 df 
 = 37,
 p
 = 0.001Short-delay recall 9.33 (3.75) 11.52 (2.96)
 
 = 2.03,
 df 
 = 38,
 p
 = 0.049Long-delay recall 9.57 (3.75) 11.89 (3.36)
 
 = 2.11,
 df 
 = 36,
 p
 = 0.042Learning slope 1.39 (0.61) 1.43 (0.56)
 
 = 0.21,
 df 
 = 37,
 p
 = 0.828Semantic cluster 0.44 (1.09) 1.9 (2.15)
 
 = 2.69,
 df 
 = 37,
 p
 = 0.01Recognition
 ‘
hits
 13.65 (1.59) 14.73 (1.28)
 
 = 2.33,
 df 
 = 37,
 p
 = 0.026Discrimination 2.65 (0.81) 3.27 (0.72)
 
 = 2.56,
 df 
 = 37,
 p
 = 0.016False positives 2.8 (3.04) 1.26 (1.88)
 
 = 0.04,
 df 
 = 37,
 p
 = 0.06Response bias 0.14 (0.28) 0.12 (0.34)
 
 = 0.87,
 df 
 = 30,
 p
 = 0.86Duration of illness 204 (237.3)
 
Medication status,
 n
 20 medication-naïve; 5 previous medication use
 
2
 N.S. Vyas et al. / Schizophrenia Research xxx (2017) xxx
 xxx
Pleasecitethisarticleas:Vyas,N.S.,etal.,D2/D3dopaminereceptorbindingwith[F-18]fallypridecorrelatesofexecutivefunctioninmedication-naïve patients with schizoph..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.05.017
 
and Doya, 2009). Human choice behavior has been conceptualized asbased on two decision systems, namely model-free and model-based,where the former system is in
󿬂
uenced by making predictions basedon previous experiences while the latter goal-directed system plans aset of actions based on future prospects. A recent study used a two-step decision choice task during fMRI combined with 18F-FDOPA PETinhealthyparticipants,reportedthathigherlevelsofpresynapticdopa-mine in the ventral striatum was associated with greater model-basedcoding in the lateral prefrontal cortices (Deserno et al., 2014). Impor-tantly, Ito et al. observed a signi
󿬁
cant negative correlation betweenthebindingpotential of dopamineD2receptors and endogenousdopa-mine synthesis rate (Ito et al., 2011) indicating that high dopa uptakeand low binding potential are alternate assessments.The goalof thecurrent studywasto investigate therelationship be-tween dopamine D2/D3 receptor density, as indexed by [
18
F]fallypride,andexecutivefunction(asmeasuredbytheWCST),andepisodicmem-ory (as measured with CVLT), in a group of medication-naïve patientswith schizophrenia and matched healthy volunteers. Because previousstudies have shown low dopamine D2/D3 receptor binding potentialin schizophrenia,we hypothesized that 1)there will be a positiveasso-ciationbetweenhighbindingpotentialandperformanceinhealthyvol-unteers, 2) this association will be less pronounced in patients withschizophreniaduetodysfunctionaldopaminedeploymentinthefrontalcortex, 3) heterogeneous dopamine de
󿬁
cits in patients with schizo-phrenia will diminish regional brain fallypride binding potential vs.neuropsychological performance correlations, and 4) there will be anassociation between binding potential and short-delay recall (model-free) in theventralstriatum in healthy volunteers, while a lower corre-lation will be found between binding potential and WCST categoriesachieved (model-based).
2. Material and methods
 2.1. Participants
Twenty-
󿬁
ve patients with schizophrenia (18 men; 7 women; agemean ± SD: 31.6 ± 12.2) were recruited from the greater Dayton,Ohio area, and assessed and consented as previously described(Buchsbaum et al., 2006; Lehrer et al., 2010a). We clinically evaluatedparticipants (Buchsbaum et al., 2006) (
n
 = 15) using the Comprehen-sive Assessment of Symptoms and History (Andreasen et al., 1992)andtheBriefPsychiatricRatingScale(Overall,1972,1976).Weclinical-lyassessedlatersubjects (
n
=18)usingthePositiveandNegativeSyn-drome Scale (Kay et al., 1987), from which BPRS scores could beestimated for the purpose of combining all subjects. Over the period of subject acquisition, other additional projects required the PANSS andthe BPRS was inadvertently not obtained on a few subjects. Howeverthe neuropsychological testing was maintained in a standard waythroughoutthisperiod.Aboard-certi
󿬁
edpsychiatrist(D.S.L.)diagnosedallsubjectsusingtheStructuredClinicalInterviewforDSM-IVAxisIDis-orders (First et al., 1996). A board-certi
󿬁
ed psychiatrist (author D.S.L.)diagnosed allsubjects.Heperformedserialstandard clinicalpsychiatricexaminations on each and utilized available collateral information(family, treating clinicians, medical records). He con
󿬁
rmed each diag-nosisusingtheStructuredClinicalInterviewforDSM-IVAxisIDisorders(SCID-I). We followed the very few schizophreniform subjects (i.e., du-rationofillnesslessthansixmonthsatthetimeofstudy)inordertode-termine whether they eventually met criteria for schizophrenia; thisdiagnostic conversion occurred in all such cases. Twenty-one subjectswerediagnosedwithschizophreniaandfourwithschizoaffectivedisor-der.Twentypatientswereabsolutelyneurolepticnaïve,ascon
󿬁
rmedbycasenotesandpsychiatricinterview,and
󿬁
vewerepreviouslymedicat-ed, although only three had a lifetime neuroleptic exposure of greaterthan two weeks. No subject had received neuroleptic within 30 daysof study. This was veri
󿬁
ed in most cases with both clinical records andinformation obtained from relatives. Subject characteristics aresummarized in Table 1. The sample size was slightly smaller than ourpreviousreport(Lehreretal.,2010a)becauseintheprocessofre-regis-tering the FDG-MRI-diffusion-tensor-fallypride images a small numberof subjects did not have the complete dataset.Nineteen healthy volunteers (12 men; 7 women; mean age ± SD:29.2 ± 9.3) were recruited via newspaper and poster advertisement.Controls were age- and sex-matched to experimental subjects. The ex-clusion criteria for the control group included: (a) a personal or familyhistory of psychiatric illness, or intellectual disabilities; (b) a personalorfamilyhistoryofhereditaryneurologicaldisorders,previousbrainin-fections,Parkinson'sdisease,signi
󿬁
cantmedicaldisorders,orheadinju-ry resulting in a loss of consciousness for
 N
1 h, and (c) DSM-IV criteriaforpsychoactivesubstanceabuseinthepreceding6monthsorthepres-ence of co-morbid Axis I disorders.
 2.2. Cognitive assessment  2.2.1. Executive function
A computerized version of the WCST:CV4 (Heaton and Staff, 2003;Milner,1963)wasadministeredtoallparticipants,whowereinstructedto matcha responsecard tooneof thefour referencecardson thebasisofthreeperceptualdimensions(shape,color,ornumber).Subjectswerenot informed of the correct sorting principle but were provided feed-back on the response (
Right
 or
 ‘
Wrong
). The following performanceindexes were of interest: (1) perseverative errors scored as number of repetitive errors; (2) total errors: total number of perseverative andnon-perseverativeerrors(presentedasT-scoreswithpositivevaluesin-dicating better performance as fewer errors); (3) categories achieved:number of rules that have been correctly identi
󿬁
ed; and (4)extradimensional shift learning: loss of set or failure to maintain set.For correlation analyses, perseverative errors and shift learning signswere reversed so that all four scores had the direction of higher valueswith higher performance.
 2.2.2. Verbal learning and memory
Verbal learning and memory were assessed with the CVLT (Delis etal., 1987; Delis et al., 2000) in which a list of 16 words (List A) is readto the participant and they are instructed to recall as many items inany order on
 󿬁
ve consecutive trials. Each item can be classi
󿬁
ed into se-mantic categories (spices & herbs, tools, fruits, or clothing). Followingtrials 1
5, the participant is presented with an interference list of 16new words (List B) over a single trial, immediately followed by ashort-delayfreerecalltrial.Aftera20mindelay,theparticipantisre-quired to recall List A. Responses that do not match the target listduring the recall trials are denoted intrusions. A 44-item yes-no rec-ognition test for List A is assessed following the long-delay recalltrial. The outcome variables included total words recalled for trials1
5, short-delay free recall, long-delay free recall (20 min delay),learning slope, recognition hits, false alarms, response bias, and dis-criminability. The CVLT also provides indexes to assess learningstrategy, including semantic clustering (recalling the items consecu-tivelyincategories)andserialclustering(recallingitemsintheorderin which they are presented).
 2.3. Imaging acquisition 2.3.1. PET scan
The participants refrained from consuming alcohol and/or caffeine4 h prior to the PET scanning session. The PET scans were acquiredusing an ECAT EXACT HR+ scanner in 3D mode (Brix et al., 1997).The subjects were placed in the scanner in a supine position. The sub- jects' head was
 󿬁
xed with a surgical tape as described earlier (Lehreret al., 2010a). A 5-min transmission scan was
 󿬁
rst acquired using a
68
Ge/ 
68
Ga rod source to correct for the attenuation of photons. The dy-namic acquisition of the PET dynamic data was initiated with a 30-sbolusinjectionof 
18
F-fallypride.Theradiopharmaceuticalwasproduced
3
N.S. Vyas et al. / Schizophrenia Research xxx (2017) xxx
 xxx
Pleasecitethisarticleas:Vyas,N.S.,etal.,D2/D3dopaminereceptorbindingwith[F-18]fallypridecorrelatesofexecutivefunctioninmedication-naïve patients with schizoph..., Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.05.017

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