Value-based decision-making of cigarette and nondrug rewards in dependent and occasional cigarette smokers: An FMRI study.

Little is known about the neural functioning that underpins drug valuation and choice in addiction, including nicotine dependence. Following ad libitum smoking, 19 dependent smokers (smoked≥10/day) and 19 occasional smokers (smoked 0.5-5/week) completed a decision-making task. First, participants stated how much they were willing-to-pay for various amounts of cigarettes and shop vouchers. Second, during functional magnetic resonance imaging, participants decided if they wanted to buy these cigarettes and vouchers for a set amount of money. We examined decision-making behaviour and brain activity when faced with cigarette and voucher decisions, purchasing (vs not purchasing) cigarettes and vouchers, and "value signals" where brain activity correlated with cigarette and voucher value. Dependent smokers had a higher willingness-to-pay for cigarettes and greater activity in the bilateral middle temporal gyrus when faced with cigarette decisions than occasional smokers. Across both groups, the decision to buy cigarettes was associated with activity in the left paracingulate gyrus, right nucleus accumbens, and left amygdala. The decision to buy vouchers was associated with activity in the left superior frontal gyrus, but dependent smokers showed weaker activity in the left posterior cingulate gyrus than occasional smokers. Across both groups, cigarette value signals were observed in the left striatum and ventromedial prefrontal cortex. To summarise, nicotine dependence was associated with greater behavioural valuation of cigarettes and brain activity during cigarette decisions. When purchasing cigarettes and vouchers, reward and decision-related brain regions were activated in both groups. For the first time, we identified value signals for cigarettes in the brain.

Assessment of Striatal Dopamine Transporter Binding in Individuals With Major Depressive Disorder: In Vivo Positron Emission Tomography and Postmortem Evidence.

Importance: Major depressive disorder (MDD) might involve dopamine (DA) reductions. The DA transporter (DAT) regulates DA clearance and neurotransmission and is sensitive to DA levels, with preclinical studies (including those involving inescapable stressors) showing that DAT density decreases when DA signaling is reduced. Despite preclinical data, evidence of reduced DAT in MDD is inconclusive. Objective: Using a highly selective DAT positron emission tomography (PET) tracer ([11C] altropane), DAT availability was probed in individuals with MDD who were not taking medication. Levels of DAT expression were also evaluated in postmortem tissues from donors with MDD who died by suicide. Design, Setting, and Participants: This cross-sectional PET study was conducted at McLean Hospital (Belmont, Massachusetts) and Massachusetts General Hospital (Boston) and enrolled consecutive individuals with MDD who were not taking medication and demographically matched healthy controls between January 2012 and March 2014. Brain tissues were obtained from the Douglas-Bell Canada Brain Bank. For the PET component, 25 individuals with current MDD who were not taking medication and 23 healthy controls recruited from McLean Hospital were included (all provided usable data). For the postmortem component, 15 individuals with depression and 14 healthy controls were considered. Intervention: PET scan. Main Outcomes and Measures: Striatal and midbrain DAT binding potential was assessed. For the postmortem component, tyrosine hydroxylase and DAT levels were evaluated using Western blots. Results: Compared with 23 healthy controls (13 women [56.5%]; mean [SD] age, 26.49 [7.26] years), 25 individuals with MDD (19 women [76.0%]; mean [SD] age, 26.52 [5.92] years) showed significantly lower in vivo DAT availability in the bilateral putamen and ventral tegmental area (Cohen d range, -0.62 to -0.71), and both reductions were exacerbated with increasing numbers of depressive episodes. Unlike healthy controls, the MDD group failed to show an age-associated reduction in striatal DAT availability, with young individuals with MDD being indistinguishable from older healthy controls. Moreover, DAT availability in the ventral tegmental area was lowest in individuals with MDD who reported feeling trapped in stressful circumstances. Lower DAT levels (and tyrosine hydroxylase) in the putamen of MDD compared with healthy controls were replicated in postmortem analyses (Cohen d range, -0.92 to -1.15). Conclusions and Relevance: Major depressive disorder, particularly with recurring episodes, is characterized by decreased striatal DAT expression, which might reflect a compensatory downregulation due to low DA signaling within mesolimbic pathways.

Assessment of Ketamine Binding of the Serotonin Transporter in Humans with Positron Emission Tomography.

Background: Comprehensive description of ketamine's molecular binding profile becomes increasingly pressing as use in real-life patient cohorts widens. Animal studies attribute a significant role in the substance's antidepressant effects to the serotonergic system. The serotonin transporter is a highly relevant target in this context, because it is central to depressive pathophysiology and treatment. This is, to our knowledge, the first study investigating ketamine's serotonin transporter binding in vivo in humans. Methods: Twelve healthy subjects were assessed twice using [11C]DASB positron emission tomography. A total of 0.50 mg/kg bodyweight ketamine was administered once i.v. prior to the second positron emission tomography scan. Ketamine plasma levels were determined during positron emission tomography. Serotonin transporter nondisplaceable binding potential was computed using a reference region model, and occupancy was calculated for 4 serotonin transporter-rich regions (caudate, putamen, thalamus, midbrain) and a whole-brain region of interest. Results: After administration of the routine antidepressant dose, ketamine showed <10% occupancy of the serotonin transporter, which is within the test-retest variability of [11C]DASB. A positive correlation between ketamine plasma levels and occupancy was shown. Conclusions: Measurable occupancy of the serotonin transporter was not detectable after administration of an antidepressant dose of ketamine. This might suggest that ketamine binding of the serotonin transporter is unlikely to be a primary antidepressant mechanism at routine antidepressant doses, as substances that facilitate antidepressant effects via serotonin transporter binding (e.g., selective serotonin reuptake inhibitors) show 70% to 80% occupancy. Administration of high-dose ketamine is widening. Based on the positive relationship we find between ketamine plasma levels and occupancy, there is a need for investigation of ketamine's serotonin transporter binding at higher doses.

Comparative assessment of 6-[18 F]fluoro-L-m-tyrosine and 6-[18 F]fluoro-L-dopa to evaluate dopaminergic presynaptic integrity in a Parkinson's disease rat model.

Because of the progressive loss of nigro-striatal dopaminergic terminals in Parkinson's disease (PD), in vivo quantitative imaging of dopamine (DA) containing neurons in animal models of PD is of critical importance in the preclinical evaluation of highly awaited disease-modifying therapies. Among existing methods, the high sensitivity of positron emission tomography (PET) is attractive to achieve that goal. The aim of this study was to perform a quantitative comparison of brain images obtained in 6-hydroxydopamine (6-OHDA) lesioned rats using two dopaminergic PET radiotracers, namely [18 F]fluoro-3,4-dihydroxyphenyl-L-alanine ([18 F]FDOPA) and 6-[18 F]fluoro-L-m-tyrosine ([18 F]FMT). Because the imaging signal is theoretically less contaminated by metabolites, we hypothesized that the latter would show stronger relationship with behavioural and post-mortem measures of striatal dopaminergic deficiency. We used a within-subject design to measure striatal [18 F]FMT and [18 F]FDOPA uptake in eight partially lesioned, eight fully lesioned and ten sham-treated rats. Animals were pretreated with an L-aromatic amino acid decarboxylase inhibitor. A catechol-O-methyl transferase inhibitor was also given before [18 F]FDOPA PET. Quantitative estimates of striatal uptake were computed using conventional graphical Patlak method. Striatal dopaminergic deficiencies were measured with apomorphine-induced rotations and post-mortem striatal DA content. We observed a strong relationship between [18 F]FMT and [18 F]FDOPA estimates of decreased uptake in the denervated striatum using the tissue-derived uptake rate constant Kc . However, only [18 F]FMT Kc succeeded to discriminate between the partial and the full 6-OHDA lesion and correlated well with the post-mortem striatal DA content. This study indicates that the [18 F]FMT could be more sensitive, with respect of [18 F]FDOPA, to investigate DA terminals loss in 6-OHDA rats, and open the way to in vivo L-aromatic amino acid decarboxylase activity targeting in future investigations on progressive PD models.

The Neurocognitive Cost of Enhancing Cognition with Methylphenidate: Improved Distractor Resistance but Impaired Updating.

A balance has to be struck between supporting distractor-resistant representations in working memory and allowing those representations to be updated. Catecholamine, particularly dopamine, transmission has been proposed to modulate the balance between the stability and flexibility of working memory representations. However, it is unclear whether drugs that increase catecholamine transmission, such as methylphenidate, optimize this balance in a task-dependent manner or bias the system toward stability at the expense of flexibility (or vice versa). Here we demonstrate, using pharmacological fMRI, that methylphenidate improves the ability to resist distraction (cognitive stability) but impairs the ability to flexibly update items currently held in working memory (cognitive flexibility). These behavioral effects were accompanied by task-general effects in the striatum and opposite and task-specific effects on neural signal in the pFC. This suggests that methylphenidate exerts its cognitive enhancing and impairing effects through acting on the pFC, an effect likely associated with methylphenidate's action on the striatum. These findings highlight that methylphenidate acts as a double-edged sword, improving one cognitive function at the expense of another, while also elucidating the neurocognitive mechanisms underlying these paradoxical effects.

Validation of semi-quantitative methods for DAT SPECT: influence of anatomical variability and partial volume effect.

The aim of this work was to evaluate the influence of anatomical variability between subjects and of the partial volume effect (PVE) on the standardized Specific Uptake Ratio (SUR) in [(123)I]FP-bib SPECT studies. To this end, magnetic resonance (MR) images of 23 subjects with differences in the striatal volume of up to 44% were segmented and used to generate a database of 138 Monte Carlo simulated SPECT studies. Data included normal uptakes and pathological cases. Studies were reconstructed by filtered back projection (FBP) and the ordered-subset expectation-maximization algorithm. Quantification was carried out by applying a reference method based on regions of interest (ROIs) derived from the MR images and ROIs derived from the Automated Anatomical Labelling map. Our results showed that, regardless of anatomical variability, the relationship between calculated and true SUR values for caudate and putamen could be described by a multiple linear model which took into account the spill-over phenomenon caused by PVE (R² ≥ 0.963 for caudate and ≥0.980 for putamen) and also by a simple linear model (R(2) ≥ 0.952 for caudate and ≥0.973 for putamen). Calculated values were standardized by inverting both linear systems. Differences between standardized and true values showed that, although the multiple linear model was the best approach in terms of variability (X² ≥ 11.79 for caudate and ≤7.36 for putamen), standardization based on a simple linear model was also suitable (X² ≥ 12.44 for caudate and ≤12.57 for putamen).

A simple algorithm for subregional striatal uptake analysis with partial volume correction in dopaminergic PET imaging.

OBJECTIVE: In positron emission tomography (PET) of the dopaminergic system, quantitative measurements of nigrostriatal dopamine function are useful for differential diagnosis. A subregional analysis of striatal uptake enables the diagnostic performance to be more powerful. However, the partial volume effect (PVE) induces an underestimation of the true radioactivity concentration in small structures. This work proposes a simple algorithm for subregional analysis of striatal uptake with partial volume correction (PVC) in dopaminergic PET imaging. METHODS: The PVC algorithm analyzes the separate striatal subregions and takes into account the PVE based on the recovery coefficient (RC). The RC is defined as the ratio of the PVE-uncorrected to PVE-corrected radioactivity concentration, and is derived from a combination of the traditional volume of interest (VOI) analysis and the large VOI technique. The clinical studies, comprising 11 patients with Parkinson's disease (PD) and 6 healthy subjects, were used to assess the impact of PVC on the quantitative measurements. Simulations on a numerical phantom that mimicked realistic healthy and neurodegenerative situations were used to evaluate the performance of the proposed PVC algorithm. In both the clinical and the simulation studies, the striatal-to-occipital ratio (SOR) values for the entire striatum and its subregions were calculated with and without PVC. RESULTS: In the clinical studies, the SOR values in each structure (caudate, anterior putamen, posterior putamen, putamen, and striatum) were significantly higher by using PVC in contrast to those without. Among the PD patients, the SOR values in each structure and quantitative disease severity ratings were shown to be significantly related only when PVC was used. For the simulation studies, the average absolute percentage error of the SOR estimates before and after PVC were 22.74% and 1.54% in the healthy situation, respectively; those in the neurodegenerative situation were 20.69% and 2.51%, respectively. CONCLUSIONS: We successfully implemented a simple algorithm for subregional analysis of striatal uptake with PVC in dopaminergic PET imaging. The PVC algorithm provides an accurate measure of the SOR in the entire striatum and its subregions, and improves the correlation between the SOR values and the clinical disease severity of PD patients.

Rotation radius dependence of 123I-FP-CIT and 123I-IBZM SPECT uptake ratios: a Monte Carlo study.

UNLABELLED: In dopamine brain SPECT, semiquantitative techniques are in use, mostly for research purposes, to calculate activity uptake in the striatum relative to the background. The measured uptake ratios depend on both acquisition and reconstruction, and one important parameter is the rotation radius of the γ-camera detectors, which affects spatial resolution. In brain SPECT research studies, the rotation radius is typically set to a constant value to maintain a constant resolution, but because of variations in patient anatomy and compliance, this is not always possible. METHODS: In this study, correction factors as a function of rotation radius are developed to correct the uptake ratios where the rotation radius has deviated from the reference value, 15 cm. Monte Carlo simulations of a digital brain phantom were used to produce images with a high and a low uptake ratio, and for both studies the rotation radius was varied between 14 and 23 cm. Two different methods, one based on 2-dimensional (2D) regions of interest of constant shape and size, and one based on predefined 3-dimensional (3D) volumes of interest, were used to calculate the semiquantitative uptake ratios. RESULTS: For the 2D method, the change in uptake ratio was 1.2%/cm for the high uptake ratio and 0.9%/cm for the low uptake ratio. The corresponding results for the 3D method were 2.1% and 1.7%, respectively. CONCLUSION: The 3D method was found to be more dependent on rotation radius than the 2D method, which was expected because of the 3D nature of the partial-volume effect. The correction factors were, however, less dependent on which of the 2 uptake ratios was simulated, which is positive for the application of the correction equations on patient data.

Assessment of striatal dopamine D2/D3 receptor availability with PET and 18F-desmethoxyfallypride: comparison of imaging protocols suited for clinical routine.

UNLABELLED: Assessment of striatal dopamine receptor availability with (18)F-desmethoxyfallypride PET is of high diagnostic utility in parkinsonism. The present study was undertaken to define the optimal clinical scan protocol with regard to quantification accuracy and scan time. METHODS: Fourteen patients with parkinsonian syndromes underwent (18)F-desmethoxyfallypride PET over 90 min. Volume-of-interest analyses were performed after spatial normalization, with the right and left caudate nuclei and putamina as target regions and the cerebellum as reference region. The estimate of target region binding potential (relative to nondisplaceable radioligand in tissue) (BP(ND)) provided by the 2-step simplified reference tissue model (SRTM2) served as the reference standard. Additional analyses included the multilinear reference tissue model 2 (MRTM2), noninvasive graphical analyses, and single-scan analyses (peak-equilibrium analysis at 35-65 min [PEA]; pseudoequilibrium analysis at 60-90 min [PsEA]). RESULTS: SRTM2 and MRTM2 yielded virtually identical results (mean BP(ND) difference = 0.1% ± 0.5%, r(2) = 1.0). Noninvasive graphical analyses with and without inclusion of the k(2)' term were affected by a small BP(ND) bias (2.5% ± 3.6% and -5.0% ± 6.7%, respectively), although correlations with SRTM2 were still excellent (r(2) = 1.0 and 0.98, respectively). In turn, single-scan analyses suffered from limited precision (PEA, mean BP(ND) bias = 0.7% ± 13.0%, r(2) = 0.90) or a considerable positive bias (PsEA, 19.2% ± 7.1%, r(2) = 0.98). Shortening scan time to 70 and 60 min resulted in an acceptable average BP(ND) change (<5% decline) for SRTM2/MRTM2 and graphical analysis with inclusion of the k(2)' term, respectively. CONCLUSION: Kinetic reference tissue model analyses of (18)F-desmethoxyfallypride PET data offer the least biased results at a well-tolerable scan duration and should thus be pursued whenever possible. Single-scan analyses may be pragmatic alternatives that, however, suffer from a relevant positive bias (PsEA) or limited precision (PEA).

Shape analysis of 123I-N-omega-fluoropropyl-2-beta-carbomethoxy-3beta-(4-iodophenyl) nortropane single-photon emission computed tomography images in the assessment of patients with parkinsonian syndromes.

PURPOSE: The purpose of this study was to show the viability and performance of a shape-based pattern recognition technique applied to I-N-omega-fluoropropyl-2-beta-carbomethoxy-3beta-(4-iodophenyl) nortropane single-photon emission computed tomography (FP-CIT SPECT) in patients with parkinsonism. METHODS: A fully automated pattern recognition tool, based on the shape of FP-CIT SPECT images, was written using Java. Its performance was evaluated and compared with QuantiSPECT, a region-of-interest-based quantitation tool, and observer performance using receiver operating characteristic analysis and kappa statistics. The techniques were compared using a sample of patients and controls recruited from a prospective community-based study of first presentation of parkinsonian symptoms with longitudinal follow up (median 3 years). RESULTS: The shape-based technique as well as the conventional semiquantitative approach was performed by experienced observers. The technique had a high level of automation, thereby avoiding observer/operator variability. CONCLUSION: A pattern recognition approach is a viable alternative to traditional methods of analysis in FP-CIT SPECT and has additional advantages.

Comparison of alpha-dihydroergocryptine and levodopa monotherapy in Parkinson's disease: assessment of changes in DAT binding with [123I]IPT SPECT.

Putative neurotoxic actions of levodopa and neuroprotective effects of dopamine agonists, as indicated by laboratory and animal studies, provide the rationale to study their effect on the progression of Parkinson's disease. Aim of this pilot study was to compare the effects of monotherapy with the dopamine agonist alpha-dihydroergocryptine (DEC) versus monotherapy with levodopa on nigrostriatal dopaminergic neurons as measured with dopamine transporter (DAT) SPECT. 25 PD patients (H&Y stages 1 to 2.5) entered this study and were treated in a randomized fashion either with DEC (101+/-39 mg) or levodopa (369+/-51 mg) monotherapy. 16/25 patients (8 per group) terminated the study after 52 weeks. In each patient SPECT investigations with [123I]IPT were performed at baseline and after 52 weeks to assess changes of specific DAT binding over time. Changes in clinical symptoms were assessed by UPDRS score. The mean annual decline rate in striatal IPT-binding was lower in the DEC group (8.4%) compared to the levodopa group (10.4%). The difference was most accentuated in the putamen (DEC: 7.3%; levodopa: 16.2%; p = 0.16). Due to the small sample size and the relatively short observation period, however, group differences did not reach a statistical significant level. The results of this pilot study suggest that as compared to levodopa monotherapy DEC may have beneficial effects on decline of dopamine transporter binding similar to those recently described for pramipexole.