D2/D3 dopamine receptor binding with [F-18]fallypride correlates of executive function in medication-naïve patients with schizophrenia
Introduction
Neurocognitive impairments are a core feature of schizophrenia, with the largest effect sizes (> 1.5 z-score differences) reported in both 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 poor functional outcome, failure in treatment interventions and limited rehabilitation (Green et al., 2000). Executive function includes multiple cognitive constructs regulated by the coordination of multi-operational neural systems and is a linchpin of cognitive ability (Bressler and Menon, 2010). It has been linked in functional neuroimaging studies to the fronto-striatal-thalamic network thought to be associated with the pervasive cognitive deficits 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 neuroanatomical structure (Alexander et al., 1986), is critical for performing tasks such as the Wisconsin Card Sorting Test (WCST) that are known to elicit performance impairments in schizophrenia, and its dysfunctional operation demonstrated in unmedicated schizophrenia patients confirmed with functional brain imaging approaches (see review and meta-analysis, Buchsbaum et al., 2005). Abnormalities in the fronto-striatal-thalamic network have also been demonstrated in functional magnetic resonance imaging (fMRI) studies of psychosis-prone individuals (Ettinger et al., 2013, Kumari et al., 2008).
While the striatum and thalamus are known to have the highest dopamine receptor concentrations in the brain, the frontal and temporal lobes also contains significant numbers of receptors on rigorous postmortem examination (Joyce et al., 1991). High-affinity dopamine receptor ligands developed for positron emission tomography (PET) make it possible to assess the fronto-striato-thalamic distribution of dopamine binding. In healthy subjects significant extra-striatal binding has been demonstrated (Buchsbaum et al., 2006, Farde et al., 1997, Lehrer et al., 2005, Mukherjee et al., 2002). In unmedicated and never-medicated subjects with schizophrenia, abnormalities in extra-striatal dopaminergic 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 earliest report by Suhara and colleagues (Suhara et al., 2002) showed lower binding potential in the thalamus in patients with schizophrenia compared with controls (in retrospect, a one-tailed test would have been p = 0.03; see their Table 1). A single photon emission computed tomography (SPECT) study using epidepride (Glenthoj et al., 2006) failed to detect binding reduction in the thalamus in patients with schizophrenia, however this negative finding may be due to lower resolution in SPECT imaging. In our studies with higher-resolution PET the decreased binding in schizophrenia was most marked in the medial dorsal nucleus isolated by tracing on co-registered MRI (Lehrer et al., 2010b), whereas in healthy subjects, the medial dorsal nucleus showed relatively higher binding compared with other thalamic nuclei (Takahashi et al., 2006).
There is increasing evidence that patients with schizophrenia exhibit impairment on executive function tasks, such as the WCST and the California Verbal Learning Test (CVLT), which is precisely aligned to non-motor fronto-striatal-thalamic circuits. Performance deficits in WCST categories achieved and perseverative errors has been widely documented in first-episode psychosis (Addington et al., 2003, Bilder et al., 2000, Brickman et al., 2004, Fagerlund et al., 2006, Mohamed et al., 1999, Riley et al., 2000, Townsend et al., 2001), and meta-analyses (Fatouros-Bergman et al., 2014, Fioravanti et al., 2005, Li, 2004). Functional MRI and PET frontal activation deficits have been found in schizophrenia (Berman et al., 1995, Patel et al., 2010, Riehemann et al., 2001) and an activation likelihood estimation meta-analysis on a series of fMRI studies using the WCST identified the frontal lobe, thalamus and striatum as important activation sites (Buchsbaum et al., 2005). The prevailing evidence from imaging studies suggests more widespread brain activations during WCST performance (Barcelo et al., 1997, Nyhus and Barcelo, 2009). An EEG study of healthy individuals revealed increased activity during task performance across all frequency bands in the frontal and temporo-parieto-occipital regions (except alpha), indicating that executive functioning skills underlying performance on the WCST may represent the operation of a more complex and widespread communication network (Gonzalez-Hernandez et al., 2002). Since dopamine projections are widespread, dopamine deficits may have profound effects on higher-order cognition (Vyas et al., 2011).
The CVLT, a measure of verbal learning and memory that relies on serial-order and semantic-cluster strategies, also involves frontal areas, as demonstrated in patients with focal lesions (Alexander et al., 2003, Baldo et al., 2002), striatal activity in PET studies of normal aging (Brickman et al., 2003), and reduced functional connectivity between the medial prefrontal, thalamus and striatum in fMRI studies of mild cognitive impairment (Liang et al., 2011). Deficits in the CVLT have consistently been reported in early-onset (Brickman et al., 2004, McClellan et al., 2004, Oie and Rund, 1999, Roofeh et al., 2006), first-episode (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 reported low dopamine receptor binding potential in the medial dorsal nucleus of the thalamus (Buchsbaum et al., 2006, Kessler et al., 2009, Lehrer et al., 2010a, Yasuno et al., 2004), and in the prefrontal cortex in patients with schizophrenia (Lehrer et al., 2010a). A study using the high-affinity radioligand [11C]FLB 457 PET also showed low D2/D3 receptor binding in the right medial thalamus in drug-naïve patients with schizophrenia compared with controls (Talvik et al., 2003).
Since excess dopaminergic activity has been hypothesized to be involved in the pathophysiology of schizophrenia, we might expect that poor WCST performance would be associated with a more active dopamine system. In subjects with schizophrenia, higher 18F-FDOPA uptake has been associated with poor task performance on the WCST perseverative errors (Meyer-Lindenberg et al., 2002). Another study showed that more perseverative errors on the CANTAB Set shifting task were significantly associated with lower binding potential in patients with schizophrenia (Fagerlund et al., 2013). Ghahremani and colleagues reported better (shorter) stop-signal reaction time associated with higher fallypride binding potential in the striatum (Ghahremani et al., 2012).
Animal models have demonstrated that the striatum plays an important role in decision-making and performing goal-directed actions (Ito and Doya, 2009). Human choice behavior has been conceptualized as based on two decision systems, namely model-free and model-based, where the former system is influenced by making predictions based on previous experiences while the latter goal-directed system plans a set of actions based on future prospects. A recent study used a two-step decision choice task during fMRI combined with 18F-FDOPA PET in healthy participants, reported that higher levels of presynaptic dopamine in the ventral striatum was associated with greater model-based coding in the lateral prefrontal cortices (Deserno et al., 2014). Importantly, Ito et al. observed a significant negative correlation between the binding potential of dopamine D2 receptors and endogenous dopamine synthesis rate (Ito et al., 2011) indicating that high dopa uptake and low binding potential are alternate assessments.
The goal of the current study was to investigate the relationship between dopamine D2/D3 receptor density, as indexed by [18F]fallypride, and executive function (as measured by the WCST), and episodic memory (as measured with CVLT), in a group of medication-naïve patients with schizophrenia and matched healthy volunteers. Because previous studies have shown low dopamine D2/D3 receptor binding potential in schizophrenia, we hypothesized that 1) there will be a positive association between high binding potential and performance in healthy volunteers, 2) this association will be less pronounced in patients with schizophrenia due to dysfunctional dopamine deployment in the frontal cortex, 3) heterogeneous dopamine deficits in patients with schizophrenia will diminish regional brain fallypride binding potential vs. neuropsychological performance correlations, and 4) there will be an association between binding potential and short-delay recall (model-free) in the ventral striatum in healthy volunteers, while a lower correlation will be found between binding potential and WCST categories achieved (model-based).
Section snippets
Participants
Twenty-five patients with schizophrenia (18 men; 7 women; age mean ± 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 evaluated participants (Buchsbaum et al., 2006) (n = 15) using the Comprehensive Assessment of Symptoms and History (Andreasen et al., 1992) and the Brief Psychiatric Rating Scale (Overall, 1972, Overall, 1976). We clinically assessed later subjects (n =
[F-18]Fallypride and WCST
In the fronto-striatal-thalamic region set, there was no significant difference between healthy volunteers and patients on the four WCST scores and no difference was confirmed with the Hotelling T2 test (F = 3.08, df = 4, 39, p = 0.23). The Hotelling T2 was at a trend level for the 13 BP values (F = 1.17, df = 13, 30, p = 0.054).
The correlation coefficients between fallypride binding potential and WCST are shown in Fig. 1. Healthy volunteers tended to show positive correlations indicating better
Discussion
To our knowledge, this study represents the first comprehensive investigation of the association between both striatal and extrastriatal D2/D3 receptor binding potential with executive function and verbal learning in medication-naïve (5 drug-free) patients with schizophrenia. The most important findings of this study are five-fold. Firstly, we found a positive correlation between binding potential and task performance on the WCST and CVLT in healthy volunteers. Secondly, we found lower or
Conflict of interest
All authors declare that they have no conflicts of interest.
Contributors
Prof Buchsbaum and Dr Lehrer designed the study. Dr Lehrer recruited, diagnosed and supervised the data collection. Dr Doninger, Dr Christian, and Dr Merrill quantified, co-registered and obtained ROI files. Dr Vyas, Dr Lehrer and Prof Buchsbaum managed the literature searches and analyses. Prof Mukherjee developed [F-18]Fallypride and supervised the synthesis. Prof Buchsbaum and Dr Vyas undertook the statistical analysis. Dr Vyas wrote the first draft of the manuscript. All authors contributed
Acknowledgements
We are grateful to all patients and healthy volunteers who participated in our study. Dr. Vyas is supported by a Winston Churchill Travelling Fellowship by the Winston Churchill Memorial Trust. Major funding was provided by the Kettering Health Network Foundation. Additional support was provided by a grant to Dr. Buchsbaum, Anatomy and function of the thalamus in schizophrenia MH60023 and by the Department of Psychiatry, University of California, San Diego. The support of the United States Air
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