Dissociable brain structural changes associated with predisposition, resilience, and disease expression in bipolar disorder.

Genetic factors are important in the etiology of bipolar disorder (BD). However, first-degree relatives of BD patients are at risk for a number of psychiatric conditions, most commonly major depressive disorder (MDD), although the majority remain well. The purpose of the present study was to identify potential brain structural correlates for risk and resilience to mood disorders in patients with BD, type I (BD-I) and their relatives. Structural magnetic resonance imaging scans were acquired from 30 patients with BD-I, 50 of their first-degree relatives (28 had no Axis I disorder, while 14 had MDD) and 52 controls. We used voxel-based morphometry, implemented in SPM5 to identify group differences in regional gray matter volume. From the identified clusters, potential differences were further examined based on diagnostic status (BD-I patients, MDD relatives, healthy relatives, controls). Whole-brain voxel-based analysis identified group differences in the left hemisphere in the insula, cerebellum, and substantia nigra. Increased left insula volume was associated with genetic preposition to BD-I independent of clinical phenotype. In contrast, increased left substantia nigra volume was observed in those with the clinical phenotype of BD-I. Changes uniquely associated with the absence of a clinical diagnosis in BD relatives were observed in the left cerebellum. Our data suggest that in BD, genetic and phenotype-related influences on brain structure are dissociable; if replicated, these findings may help with early identification of high-risk individuals who are more likely to transition to syndromal states.

Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100,907 PET and non-invasive kinetic analyses.

BACKGROUND: [(11)C]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT(2A) receptor quantification in vivo. Studies suggest that [(11)C]MDL100,907 PET may be quantified by non-invasive reference tissue analyses using cerebellum as reference region. We systematically investigated the validity of such analyses. METHODS: Five healthy volunteers underwent [(11)C]MDL100,907 PET at baseline and after mirtazapine pre-treatment. Regional time-activity curves of 10 regions of interest (ROI) were analyzed for binding potential (BP(ND)) and mirtazapine receptor occupancy (Occ) using: simplified reference tissue model (SRTM), multi-linear reference tissue model (MRTM), their two-parameter versions (SRTM2/MRTM2), non-invasive graphical analysis (NIGA) and a tissue activity concentration ratio. NIGA was also applied voxel-wise to generate BP(ND) maps. These methods were compared with a two-tissue compartment model with arterial input function (2TCM) Results: SRTM and MRTM frequently failed to yield reliable results. SRTM2 and MRTM2 gave virtually identical estimates of BP(ND), which were highly correlated with 2TCM analyses (R(2)>or=0.86) although with negative bias (-29+/-27% at baseline across all ROI). NIGA was less biased (-19+/-16%) and better correlated with 2TCM (R(2)>or=0.93). Regarding Occ, NIGA and SRTM2/MRTM2 showed comparable mean biases (-11+/-27% vs. -7+/-47%) but correlation with 2TCM was higher for NIGA (R(2)=0.90 vs. 0.77). NIGA parametric maps (analysed using identical ROI) resulted in moderate bias in BP(ND) (-26+/-22%; R(2)>or=0.88) and Occ (-17+/-36%; R(2)=0.78). Estimates obtained from tissue ratios performed least favourably. CONCLUSIONS: NIGA is well suited for analysis of [(11)C]MDL100,907 PET studies, yielding estimates of 5-HT(2A) receptor availability and changes that are highly correlated with results from invasive 2TCM analyses. This should greatly enhance the applicability of 5-HT(2A) receptor PET studies.

Acute effect of the anti-addiction drug bupropion on extracellular dopamine concentrations in the human striatum: an [11C]raclopride PET study.

Bupropion is an effective medication in treating addiction and is widely used as an aid to smoking cessation. Bupropion inhibits striatal dopamine reuptake via dopamine transporter blockade, but it is unknown whether this leads to increased extracellular dopamine levels at clinical doses in man. The effects of bupropion on extracellular dopamine levels in the striatum were investigated using [(11)C]raclopride positron emission tomography (PET) imaging in rats administered saline, 11 or 25 mg/kg bupropion i.p. and in healthy human volunteers administered either placebo or 150 mg bupropion (Zyban Sustained-Release). A cognitive task was used to stimulate dopamine release in the human study. In rats, bupropion significantly decreased [(11)C]raclopride specific binding in the striatum, consistent with increases in extracellular dopamine concentrations. In man, no significant decreases in striatal [(11)C]raclopride specific binding were observed. Levels of dopamine transporter occupancy in the rat at 11 and 25 mg/kg bupropion i.p. were higher than predicted to occur in man at the dose used. Thus, these data indicate that, at the low levels of dopamine transporter occupancy achieved in man at clinical doses, bupropion does not increase extracellular dopamine levels. These findings have important implications for understanding the mechanism of action underlying bupropions' therapeutic efficacy and for the development of novel treatments for addiction and depression.

Further evaluation of the carbon11-labeled D(2/3) agonist PET radiotracer PHNO: reproducibility in tracer characteristics and characterization of extrastriatal binding.

[(11)C]-(+)-PHNO is a new dopamine D(2/3) receptor agonist radiotracer which has been successfully used to measure D(2/3) receptor availability in experimental animals and man. Here we report in vivo evaluation in the rat of the biodistribution, metabolism, specificity, selectivity, and dopamine sensitivity of carbon11-labeled PHNO ([(11)C]-3-PHNO) produced by an alternative radiochemical synthesis method. [(11)C]-3-PHNO showed rapid metabolism and clearance from most peripheral organs and tissues. [(11)C]-3-PHNO, but not its polar metabolite, readily crossed the blood-brain barrier and showed high levels of uptake in the D(2/3)-rich striatum. Pretreatment with unlabeled PHNO and the D(2/3) receptor antagonist raclopride indicated that binding in the striatum was specific and selective to D(2/3) receptors. PET studies in anesthetized rats revealed significant reductions in [(11)C]-3-PHNO binding in the striatum following amphetamine administration, indicating sensitivity to increases in endogenous dopamine concentrations. D(2/3) antagonist pretreatment additionally indicated moderate levels of [(11)C]-3-PHNO specific binding in several extrastriatal brain areas-most notably the olfactory bulbs and tubercles, thalamus, and hypothalamus. Of particular interest, approximately 30% of [(11)C]-3-PHNO signal in the cerebellum-a region often used as a "low-binding" reference region for PET quantification-was attributable to specific signal. These data demonstrate that [(11)C]-3-PHNO shows similar tracer characteristics to [(11)C]-(+)-PHNO, but additionally indicate that radiolabeled PHNO may be used to estimate D(2/3) receptor availability in select extrastriatal brain regions with PET.

Can recreational doses of THC produce significant dopamine release in the human striatum?

BACKGROUND: Cannabis use in early adolescence may be a risk factor for development of schizophrenia. In animals, Delta9-tetrahydrocannabinol (THC) increases the rate of dopamine neuronal firing and release in the striatum. Thus cannabis use may increase dopamine release in the human striatum leading to vulnerability to psychosis. AIMS: To investigate whether THC, the main psychoactive component of cannabis, can produce dopamine release in the human striatum. METHODS: Thirteen healthy volunteers, with previous cannabis experience, underwent two [11C]-raclopride positron emission tomography (PET) scans to indirectly measure striatal dopamine levels following either 10 mg THC or placebo. RESULTS: Although THC markedly increased psychosis-like symptoms on the Psychotomimetic States Inventory (PSI), there was no significant effect of THC on [11C]-raclopride binding. CONCLUSION: In the largest study of its kind so far, we have shown that recreational cannabis users do not release significant amounts of dopamine from an oral THC dose equivalent to a standard cannabis cigarette. This result challenges current models of striatal dopamine release as the mechanism mediating cannabis as risk factor for schizophrenia.

Human 5-HT transporter availability predicts amygdala reactivity in vivo.

The amygdala plays a central role in fear conditioning, emotional processing, and memory modulation. A postulated key component of the neurochemical regulation of amygdala function is the neurotransmitter 5-hydroxytryptamine (5-HT), and synaptic levels of 5-HT in the amygdala and elsewhere are critically regulated by the 5-HT transporter (5-HTT). The aim of this study was to directly examine the relationship between 5-HTT availability and amygdala activity using multimodal [positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)] imaging measures in the same individuals. Healthy male volunteers who had previously undergone an [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile ([11C]-DASB) PET scan to determine 5-HTT availability completed an fMRI emotion recognition task. [11C]-DASB binding potential values were calculated for the amygdala using arterial input function and linear graphical (Logan) analysis. fMRI was performed on a 3T Philips Intera scanner, and data were analyzed using SPM2 (Wellcome Department Imaging Neuroscience, University College London). Percentage signal change during the task was extracted from the amygdala using MarsBaR (Brett et al., 2002). fMRI analysis revealed significant amygdala activation during the emotion recognition task. Region of interest analyses demonstrated a significant negative correlation between fMRI signal change in the left amygdala and 5-HTT availability in the left amygdala, with 5-HTT availability accounting for approximately 42% of the variability in left amygdala activity. Our novel in vivo data highlight the central importance of the serotonergic system in the responsiveness of the human amygdala during emotional processing.

Modulation of striatal dopamine release by 5-HT2A and 5-HT2C receptor antagonists: [11C]raclopride PET studies in the rat.

RATIONALE: Antagonism at serotonin 5-HT2A and 5-HT2C receptors modulates cortical and striatal dopamine (DA) release and may underlie some aspects of the clinical efficacy of 'atypical' antipsychotic compounds. However, it is not known whether 5-HT2A/2C receptor-mediated modulation of DA release can be quantified with non-invasive neurochemical imaging, as would be required for investigation of these processes in man. OBJECTIVE: The objective of the study was to perform a feasibility study in the rat in order to determine whether 5-HT2A/2C modulation of DA release can be observed using positron emission tomography (PET) imaging. MATERIALS AND METHODS: Rats were administered with either vehicle, a combined 5-HT2A/2C antagonist (ketanserin, 3 mg/kg i.p.), or the more selective 5-HT2C antagonist SB 206,553 (10 mg/kg i.p.) 30 min before administration of the PET DA D2 receptor radiotracer [11C]raclopride ( approximately 11 MBq) and were then scanned for 60 min using a quad-high-density avalanche chamber small animal tomograph. Using the same technique, modulation of amphetamine (4 mg/kg)-induced decreases in [11C]raclopride binding by 5-HT2A antagonism (SR 46349B, 0.2 mg/kg i.v.) was also determined. RESULTS: Consistent with the increase in DA release measured by others using microdialysis, 5-HT2C antagonism markedly reduced striatal [11C]raclopride binding (p < 0.003), while amphetamine-induced reductions in striatal [11C]raclopride binding (p < 0.001) were attenuated by 5-HT2A antagonist administration (p = 0.04). CONCLUSIONS: These results inform the feasibility of monitoring 5-HT2A/2C receptor-mediated modulation of DA systems in man using PET and, more generally, demonstrate that D2 radiotracer PET imaging may be used to monitor the efficacy of new DA modulators in attenuating stimulated DA release.

Dopamine D2 receptor occupancy levels of acute sulpiride challenges that produce working memory and learning impairments in healthy volunteers.

RATIONALE: In humans, the effects of dopaminergic agents administered systemically are less clear-cut than studies in experimental animals where agents can be applied locally in the brain. DA receptor occupancy could clearly contribute to the variance in findings, although this is typically not known. OBJECTIVES: The objective of the study was to measure the DA D2 receptor occupancy of sulpiride 200 and 400 mg and relate this to changes in task performance. MATERIALS AND METHODS: Positron emission tomography scans were acquired in ten healthy volunteers with [11C]-raclopride. Striatal drug occupancy was calculated as the percentage change in binding potential between placebo and drug scans. All volunteers received placebo and sulpiride 400 mg, with four receiving 200 mg on a third session. Immediate post-scan neuropsychological assessment included working memory and learning tasks. RESULTS: Striatal sulpiride occupancy was approximately 17% (200 mg) and approximately 28% (400 mg), with similar occupancy within the midbrain. Neuropsychological data analysis was restricted to the higher dose (n = 10). Accuracy on the spatial working memory and spatial learning tasks was impaired after the drug, and the former was inversely related to occupancy. CONCLUSION: Doses of sulpiride typically used in human cognitive studies produced low levels of DA D2 receptor occupancy compared to that considered efficacious in the treatment of schizophrenia. The levels of occupancy were sufficient to replicate impairments on a spatial working memory task and impair spatial learning. The relationship between occupancy and working memory was suggestive of presynaptic effects, although the precise mechanism underlying the impairment will require studies of wider ranges of occupancy within and outside of the striatum.

Classification of schizophrenic patients and healthy controls using [18F] fluorodopa PET imaging.

Striatal dopaminergic overactivity has been implicated in the pathophysiology of schizophrenia on the basis of in vivo neuroimaging studies. In particular, elevated striatal dopamine synthesis and storage has been repeatedly demonstrated in schizophrenia using the radiotracer 6-[18F] fluoro-l-DOPA ([18F] DOPA) and positron emission tomography (PET). Conventionally analysed [18F] DOPA PET imaging lacks the sensitivity or specificity to be used diagnostically. The aim of this study was to determine if the application of an Artificial Neural Network (ANN) would improve classification of images, and increase the sensitivity and specificity of [18F] DOPA as a potential diagnostic test for schizophrenia. We tested an ANN model in the discrimination of schizophrenic patients from normal controls using [18F] DOPA rate constants within the anterior-posterior subdivisions of the striatum, and compared the model with a general linear analysis of the same data. Participating in the study were 19 patients diagnosed with paranoid schizophrenia and 31 healthy subjects. Maximum classification was achieved using laterality quotients, - the ANN model correctly identified 94% of the controls and 89% of the patients, equivalent to 89% sensitivity and 94% specificity. Using all bilateral striatal regions correctly categorised 74% of the controls and 84% of the patients, equivalent to 84% sensitivity and 74% specificity. In comparison, the general linear analysis performed poorly, correctly classifying only 58% of the controls and 63% of the patients. Overall, these analyses have shown the potential utility of pattern recognition tools in the classification of psychiatric patients based upon molecular imaging of a single target.

Measurement of methylphenidate-induced change in extrastriatal dopamine concentration using [11C]FLB 457 PET.

[(11)C]FLB 457 is a very high-affinity radiotracer that allows the measurement of dopamine D(2/3) receptor availability in regions of the brain where densities are very low, such as the cerebral cortex. It is not known if [(11)C]FLB 457 binding is sensitive to the concentration of endogenous dopamine in humans in a manner analogous to [(11)C]raclopride and [(123)I]IBZM in the striatum. To test this possibility, extrastriatal [(11)C]FLB 457 binding was measured at baseline and after the oral administration of 40 to 60 mg of the psychostimulant methylphenidate (MP) in 12 healthy volunteers using positron emission tomography (PET) in a balanced-order, double-blind design. The dynamic PET data were quantified using a two-tissue compartment model with a metabolite-corrected arterial plasma input function. Two volunteers were excluded because of excessive head movement. In the remainder, MP caused significant reductions in the volume of distribution (VD) in temporal and frontal cortical regions and thalamus, suggesting that [(11)C]FLB 457 binding is sensitive to endogenous dopamine concentration. Moreover, the change in [(11)C]FLB 457 binding after MP correlated with the dose of MP (in mg/kg body weight) in all regions assessed. We conclude that MP in doses within the therapeutic range for the treatment of attention deficit hyperactivity disorder causes increases in dopamine concentrations in extrastriatal regions and that [(11)C]FLB 457 PET may be a useful tool for the assessment of change in dopamine concentration in these areas in humans.

Validation of a tracer kinetic model for the quantification of 5-HT(2A) receptors in human brain with [(11)C]MDL 100,907.

The positron emission tomography (PET) ligand [(11)C]MDL 100,907 has previously been introduced to image the serotonin 2A (5-HT(2A)) receptor in human brain. The aim of this work was to contribute to the verification of the tracer kinetic modelling in human studies. Five healthy volunteers were scanned twice after intravenous bolus injection of approximately 370 MBq [(11)C]MDL 100,907 using dynamic PET. One scan was performed under baseline condition, the other scan commenced 90 mins after a single oral dose of 30 mg of the antidepressant mirtazapine, which binds to the 5-HT(2A) receptor. There did not appear to be radiolabelled metabolites of [(11)C]MDL 100,907 in human plasma, which are likely to cross the blood-brain barrier. Total volumes of distribution VD in 11 different brain regions were estimated using a reversible, two tissue, four rate constants compartment model with a variable fractional blood volume term and the metabolite-corrected plasma input function. There were no significant changes of the VD in the cerebellum between the baseline and the blocked scans confirming the cerebellum as a region devoid of displaceable binding. Regional estimates of binding potential were then obtained indirectly using the cerebellar VD and occupancies calculated. The mean occupancy with this clinically effective dose of mirtazapine was 60% without significant regional differences. This study confirmed the use of an arterial input kinetic model for the quantification of 5-HT(2A) receptor binding with [(11)C]MDL 100,907 and the use of the cerebellum as a reference region for the free and nonspecific binding.

Quantification of PET studies with the very high-affinity dopamine D2/D3 receptor ligand [11C]FLB 457: re-evaluation of the validity of using a cerebellar reference region.

The very high-affinity position emission tomography (PET) radioligand [(11)C]FLB 457 was developed in order to study extrastriatal tissues, where the density of dopamine D(2)/D(3) receptors is one to two orders of magnitude lower than in the striatum. The present study investigated the validity of using the cerebellum as a reference region. Ten healthy volunteers underwent a 90-min dynamic PET study after the bolus injection of [(11)C]FLB 457. The total volume of distribution (VD(t)) was estimated for the thalamus, hippocampus, frontal cortex, and cerebellum using a two-tissue compartmental model with a metabolite-corrected arterial plasma input function. VD(t) was sensitive to co-injected stable FLB 457 in all regions, including the cerebellum. Ex vivo saturation studies were also conducted in 17 rats where the dose of stable ligand was varied over five orders of magnitude. Specific binding was estimated to account for more than half of the rat cerebellar uptake of [(11)C]FLB 457, questioning the latter as an estimate of nonspecific binding in human PET studies. To check whether the cerebellum is a reference region, the binding potential (BP) was calculated either from the VD(t) ratio or using the simplified reference tissue model (SRTM). A non-negligible density of D(2)/D(3) receptors in the cerebellum was shown to lead to underestimation of BP as well as erroneous estimation of differential occupancies. Binging potential estimates from the SRTM were found to be sensitive to changes in cerebral blood flow, providing further evidence for caution in the use of the cerebellum as a reference region in measures of [(11)C]FLB 457 binding.

Extrastriatal D2 and striatal D2 receptors in depressive illness: pilot PET studies using [11C]FLB 457 and [11C]raclopride.

BACKGROUND: Reduced dopaminergic function may occur in depressive disorders. In this paper the results of two pilot studies examining different aspects of the dopamine system in depression are presented. First, the binding of [(11)C]FLB 457 to extrastriatal D(2) receptors was measured in a group of depressed patients. Second, the hypothesis that selective serotonin reuptake inhibiting (SSRI) antidepressants affect the striatal binding of [(11)C]raclopride was tested. METHODS: In the first study the binding of [(11)C]FLB 457 was compared between 7 people with depression and 7 healthy controls. In the second study the binding of [(11)C]raclopride to striatal D(2/3) receptors was compared between 8 people taking SSRI antidepressant medication and 8 healthy controls. RESULTS: There was no difference in the binding of [(11)C]FLB 457 between the two groups. [(11)C]raclopride binding was reduced in the dorsal striatum of people taking antidepressants suggesting either that D(2/3) expression was reduced, or that dopamine release was increased, compared to untreated controls. LIMITATIONS: The depressed patients were not severely depressed and were not matched for gender with controls. In the raclopride group the patients and controls were not matched by gender and were taking different SSRI antidepressants. CONCLUSION: We found no support for the hypothesis that dopamine D(2) receptor expression is altered in extrastriatal brain regions in depression. SSRI antidepressants were associated with reduced [(11)C]raclopride binding in the dorsal striatum supporting the hypothesis that therapeutic effects of such drugs may, in part, be due to changes in the dopamine system.

Molecular imaging studies of the striatal dopaminergic system in psychosis and predictions for the prodromal phase of psychosis.

The dopamine hypothesis has been the major pathophysiological theory of psychosis in recent decades. Molecular imaging studies have provided in vivo evidence of increased dopamine synaptic availability and increased presynaptic dopamine synthesis in the striata of people with psychotic illnesses. These studies support the predictions of the dopamine hypothesis, but it remains to be determined whether dopaminergic abnormalities pre-date or are secondary to the development of psychosis. We selectively review the molecular imaging studies of the striatal dopaminergic system in psychosis and link this to models of psychosis and the functional subdivisions of the striatum to make predictions for the dopaminergic system in the prodromal phase of psychosis.

A functional genetic variation of the serotonin (5-HT) transporter affects 5-HT1A receptor binding in humans.

In humans, 5-HT1A receptors are implicated in anxiety and depressive disorders and their treatment. However, the physiological and genetic factors controlling 5-HT1A receptor expression are undetermined in health and disease. In this study, the influence of two genetic factors on 5-HT1A receptor expression in the living human brain was assessed using the 5-HT1A-selective positron emission tomography (PET) ligand [11C]WAY 100635. After the genotyping of 140 healthy volunteers to study population frequencies of known single nucleotide polymorphisms (SNPs) in the 5-HT1A receptor gene, the influence of the common SNP [(-1018) C>G] on 5-HT1A receptor expression was examined in a group of 35 healthy individuals scanned with [11C]WAY 100635. In the PET group, we also studied the influence of a common variable number tandem repeat polymorphism [short (S) and long (L) alleles] of the 5-HT transporter (5-HTT) gene on 5-HT1A receptor density. Whereas, the 5-HT1A receptor genotype did not show any significant effects on [11C]WAY 100635 binding, 5-HT1A receptor binding potential values were lower in all brain regions in subjects with 5-HTTLPR short (SS or SL) genotypes than those with long (LL) genotypes. Although the PET groups are necessarily a small sample size for a genetic association study, our results demonstrate for the first time that a functional polymorphism in the 5-HTT gene, but not the 5-HT1A receptor gene, affects 5-HT1A receptor availability in man. The results may offer a plausible physiological mechanism underlying the association between 5-HTTLPR genotype, behavioral traits, and mood states.

Correction of head movement on PET studies: comparison of methods.

UNLABELLED: Head movement presents a continuing problem in PET studies. Head restraint minimizes movement but is unreliable, resulting in the need to develop alternative strategies. These include frame-by-frame (FBF) realignment or use of motion tracking (MT) during the scan to realign PET acquisition data. Here we present a comparative analysis of these 2 methods of motion correction. METHODS: Eight volunteers were examined at rest using (11)C-raclopride PET with the radioligand administered as a bolus followed by constant infusion to achieve steady state. Binding potential (BP) was estimated using the ratio method during 2 periods of the scan at steady state. Head movement was compensated by using coregistration between frames (FBF) and 3 methods using MT measurements of head position acquired with a commercially available optical tracking system. RESULTS: All methods of realignment improved test-retest reliability and noise characteristics of the raw data, with important consequences for the power to detect small changes in radiotracer binding, and the potential to reduce false-positive and false-negative results. MT methods were superior to FBF realignment using coregistration on some indices. CONCLUSION: Such methods have considerable potential to improve the reliability of PET data with important implications for the numbers of volunteers required to test hypotheses.

Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635.

BACKGROUND: Research from neuroendocrine challenge and other indirect studies has suggested increased central 5-HT function in chronic fatigue syndrome (CFS) and increased 5-HT1A receptor sensitivity. We assessed brain 5-HT1A receptor binding potential directly using the specific radioligand [11C]WAY-100635 and positron emission tomography (PET). METHODS: We selected 10 patients from a tertiary referral clinic who fulfilled the CDC consensus criteria for CFS. To assemble a homogenous group and avoid confounding effects, we enrolled only subjects who were completely medication-free and did not have current comorbid psychiatric illness. We also scanned 10 healthy control subjects. RESULTS: There was a widespread reduction in 5-HT1A receptor binding potential in CFS relative to control subjects. This was particularly marked in the hippocampus bilaterally, where a 23% reduction was observed. CONCLUSIONS: There is evidence of decreased 5-HT1A receptor number or affinity in CFS. This may be a primary feature of CFS, related to the underlying pathophysiology, or a finding secondary to other processes, such as previous depression, other biological changes or the behavioral consequences of CFS.

Sustained attention-deficit confirmed in euthymic bipolar disorder but not in first-degree relatives of bipolar patients or euthymic unipolar depression.

BACKGROUND: Cognitive dysfunction persists in the euthymic phase of bipolar disorder and may provide a marker of underlying neuropathology and disease vulnerability. This study aimed to replicate a deficit in sustained attention in euthymic bipolar patients and investigate sustained attention in first-degree relatives of bipolar probands and in remitted patients with major depressive disorder. METHODS: The rapid visual information processing (RVIP) task was used to measure sustained attention in 15 euthymic patients with bipolar disorder and 15 control subjects in experiment 1 and in 27 first-degree relatives of bipolar probands, 15 remitted patients with major depressive disorder, and 46 control subjects in experiment 2. RESULTS: Sustained attention deficit was confirmed in the euthymic bipolar patients in experiment 1, but the deficit was not statistically significant in remitted major depressed patients or in the relatives of bipolar probands. CONCLUSIONS: A deficit of sustained attention is not present in patients with recurrent major depression tested during remission nor is it discriminable in the first-degree relatives of bipolar probands. Thus, the confirmed abnormality in euthymic bipolar patients may be acquired as a consequence of bipolar illness. However, future studies of relatives will require larger sample sizes to exclude or utilize small genetic effects.

The effects of acute tyrosine and phenylalanine depletion on spatial working memory and planning in healthy volunteers are predicted by changes in striatal dopamine levels.

RATIONALE: Dopamine (DA) is considered important in the modulation of tasks of spatial working memory. However, the findings from studies in humans to date are mixed. While this may be due to the characteristics of the tasks used, it is also possible that these findings are explained by variable central effects of the manipulations used. OBJECTIVE: To test the effects of acute tyrosine and phenylalanine depletion (TPD, which reduces synthesis and release of brain DA) on cognitive function and relate changes in performance accuracy to the central effects of TPD measured with [11C]raclopride positron emission tomography (PET). METHODS: Fourteen participants were given tests of spatial working memory, planning, verbal memory span and trial-and-error learning after acute TPD, seven of whom also received PET scans to measure changes in striatal DA levels. RESULTS: Although TPD produced a clear reduction in tyrosine and phenylalanine availability to the brain, no impairments on any of the cognitive tests were observed. However, changes in spatial working memory and planning accuracy after TPD showed a highly significant relationship with the changes in striatal DA levels. CONCLUSIONS: Our findings suggest that the effects of TPD on spatial working memory and planning may be unreliable due to the variability of the changes in brain DA levels achieved with this manipulation.

Sulpiride and mnemonic function: effects of a dopamine D2 receptor antagonist on working memory, emotional memory and long-term memory in healthy volunteers.

There is now substantial evidence from animal studies showing modulation of cognitive performance after administration of dopaminergic agents. Previous studies have focused on cognitive functions such as working memory (WM), with particular reference to spatial processing. However, to date, studies in normal human volunteers have proved inconsistent. We have therefore tested the effects of the dopamine D2 receptor antagonist sulpiride (400 mg) on WM and learning tasks, including those using auditory, spatial or non-spatial stimuli. A further aim was to explore a broader role of the dopaminergic system in mnemonic function by examining long-term and emotional memory. Eighteen healthy male participants were given a battery of cognitive tests after oral sulpiride or placebo, using the cross-over design. WM was assessed using a spatial searching task, and a task of auditory counting with distraction. Tasks that did not emphasize WM were spatial and non-spatial trial-and-error learning, long-term spatial memory and emotional memory. After dopamine D2 receptor blockade, performance was not impaired on the spatial WM (SWM) task, but was impaired on the auditory counting task with distraction. Sulpiride did not impair, but rather appeared to enhance trial-and-error learning overall. Thus, we were unable to support the notion that dopaminergic modulation preferentially influences spatial over non-spatial processing during learning. In addition, recognition was impaired in the emotional memory task after encoding on drug compared to placebo. These findings question the precise role of dopamine D2 receptor modulation on WM, and highlight the need for sensitive tests to study dopaminergic modulation of emotional processing.