The human striatum in schizophrenia. II. Increased number of striatal neurons in schizophrenics

In neuropathological studies of schizophrenia, alterations of the basal ganglia are one main topic. Using the optical dissector, we performed an unbiased estimation of neurons and glia cells in the human striatum. To rule out an influence of age and gender, the brains of 9 male schizophrenic patients younger than 65 were closely matched in age with the brains of 9 male control persons. Absolute neuron numbers of the striatum and its subdivisions putamen and nucleus caudatus/nucleus accumbens of both hemispheres were compared between both groups, as were absolute glia cell numbers and the calculated glia index. We found a significant increase of absolute striatal neuron numbers in the schizophrenic group on the right side (P = 0.008^**) and only a trend to higher absolute striatal neuron numbers on the left side. In a further analysis, the significant increase of absolute striatal neuron numbers in the right striatum of the schizophrenic group was only discernible for the nucleus caudatus/nucleus accumbens complex (P = 0.01^*) and not for the putamen. Absolute striatal glia cell numbers did not differ significantly between both groups, neither on the right nor on the left side. There was only a trend towards a smaller glia index on both sides. Cortical developmental disturbances with a consecutive reduction of naturally occurring cell death during development could be responsible for this increase in absolute striatal neuron numbers in schizophrenics.     

Dopamine D2 receptor binding in drug-naïve patients with schizophrenia examined with raclopride-C11 and positron emission tomography

The aim was to test the dopamine hypothesis of schizophrenia in a further analysis of D₂-like dopamine binding using the radioligand [¹¹C]raclopride and high resolution 3-dimensional (3D) PET. Eighteen drug-naive patients with schizophrenia and seventeen control subjects were examined. The D₂ binding potential (BP) in the putamen, the caudate and the thalamus was calculated using the simplified reference tissue model. The volume of regions of interest was controlled for by MRI. Symptoms were rated with the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). No significant group differences were found for D₂ BP in the putamen or in the caudate and there was no significant hemispheric difference for any region. In the right thalamus the D₂ BP was significantly lower in patients as compared to control subjects, whereas a numerical difference did not reach statistical significance for the left thalamus. There was no significant correlation between D₂ BP and total PANSS score in any region. There was a highly significant age effect in the caudate and in the putamen, but not in the thalamus. In this relatively large PET study of exclusively drug-naive schizophrenic patients, a lower D₂ BP in the right thalamus was found in the patient group. This finding is in agreement with two previous studies in Sweden and in Japan using the high-affinity radioligand [¹¹C]FLB 457 and provide further support for a role of dopamine in the thalamus related to the pathophysiology of schizophrenia.     

An increase in [ ] CGS21680 binding in the striatum of postmortem brains of chronic schizophrenics

We measured adenosine 2a receptors in basal ganglia of 13 schizophrenics and 10 controls, using [ ] CGS21680 as a ligand for the receptor binding assay. There was a significant increase in the specific [ ] CGS21680 binding in the putamen and caudate, but not in the globus pallidus of externa, of the schizophrenic patients, compared to those of controls. These results provide evidence suggesting that adenosine 2a receptors play a role in the pathophysiology of schizophrenia.     

Levodopa-induced striatal activation in Parkinson's disease: A functional MRI study

ObjectiveTo assess the effect of a single levodopa dose (200 mg levodopa, 50 mg carbidopa = sdLD) on cortical and subcortical motor-circuit activation during bimanual grip force in patients with Parkinson's disease (PD).Patients and methodsWe studied 12 right-handed patients with PD (Hoehn–Yahr stages I–II) after a period of at least 12 h without medication (OFF state) and a second time 1 h after oral administration of sdLD (ON state) using functional magnetic resonance imaging (fMRI). Blood-oxygenation-level-dependency (BOLD) fMRI was measured while participants underwent two unilateral and two bimanual grip force movements with a defined movement amplitude and force (10 N) in a block design. 12 age matched healthy subjects were studied as controls (without administration of sdLD).ResultsBimanual grip force tasks activated a specific pattern of cortical and subcortical structures in all patients during the OFF state and after levodopa administration with statistically significant differences in putamen and thalamus comparing the OFF and ON condition. In contrast, no such significant changes were observed in cortical structures. Between-group analysis revealed higher putaminal activity in controls compared to OFF state in bimanual tasks, while these differences disappeared after administration of levodopa.ConclusionsOur results indicate that the putamen and thalamus are the regions within the cortico-subcortical motor-circuit with most prominent response to levodopa. In our study, cortical motor areas did not respond to levodopa as one could have expected from previous studies. These findings contribute to the increasing evidence that an extended model of the underlying pathophysiology of motor dysfunctions in PD is warranted.     

Evidence of altered membrane phospholipid metabolism in the anterior cingulate cortex and striatum of patients with bipolar disorder I: A multi-voxel 1H MRS study

BackgroundPrevious proton magnetic resonance spectroscopy (¹H MRS) studies have reported elevated glycerophosphocholine plus phosphocholine (GPC+PC) in the basal ganglia of patients with bipolar disorders (BD), which implicates an imbalance between synthesis and degradation activity of neuronal and glia membrane phospholipids (MPLs). However, the full extent of altered metabolites of MPLs in subareas within the basal ganglia, such as caudate and putamen, as well as anterior cingulate cortex (ACC) of BD patients is poorly understood.MethodsMulti-voxel ¹H MRS measurements were acquired in 50 type-one BD (BD-I) and 44 healthy controls (HC) on a 3-T MRI scanner. Four different anatomically defined voxels covering ACC, caudate and putamen were systematically extracted and quantified using LCModel. Group differences in absolute GPC+PC and other metabolites were tested with age and gender as covariates.ResultsBD-I patients had higher GPC+PC levels in the anterior-dorsal ACC (p = 0.037), caudate (p = 0.005) and putamen (p = 0.004) compared to HC. GPC+PC levels in the caudate were elevated most significantly in currently unmediated BD-I patients (p = 0.022) and were positively correlated with HAM-D scores (r = 0.51, p = 0.005). PCr+Cr and myo-inositol levels were also significantly higher in the caudate head (F(1,45) = 6.010, p = 0.018) of patients compared to HC. NAA and glutamate levels were not significantly different between BD-I and HC in these regions (p > 0.05).ConclusionThe increased GPC+PC in BD-I patients may reflect an imbalance in the MPL metabolism. Caudate GPC+PC levels may be a potential biomarker for depressive symptoms in BD.     

Basal ganglia volume in unmedicated patients with schizophrenia is associated with treatment response to antipsychotic medication

We investigated the relationship between basal ganglia volume and treatment response to the atypical antipsychotic medication risperidone in unmedicated patients with schizophrenia. Basal ganglia volumes included the bilateral caudate, putamen, and pallidum and were measured using the Freesurfer automated segmentation pipeline in 23 subjects. Also, baseline symptom severity, duration of illness, age, gender, time off medication, and exposure to previous antipsychotic were measured. Treatment response was significantly correlated with all three regions of the bilateral basal ganglia (caudate, putamen, and pallidum), baseline symptom severity, duration of illness, and age but not gender, time off antipsychotic medication, or exposure to previous antipsychotic medication. The caudate volume was the basal ganglia region that demonstrated the strongest correlation with treatment response and was significantly negatively correlated with patient age. Caudate volume was not significantly correlated with any other measure. We demonstrated a novel finding that the caudate volume explains a significant amount of the variance in treatment response over the course of 6 weeks of risperidone pharmacotherapy even when controlling for baseline symptom severity and duration of illness.     

Neuronal activity in the striatum and pallidum of primates related to the execution of externally cued reaching movements

We studied changes in basal ganglia neuronal activity associated with reaching movements of the arm in two monkeys. Data were obtained from 427 single neuronal units in putamen, 199 in caudate nucleus, and 216 in globus pallidus with multiwire electrodes allowing simultaneous recordings from multiple neurons. In all structures, changes in activity related to movement occurred most often after the onset of EMG: 43% of tested neurons in the putamen, 32% in the caudate nucleus, and 38% in the globus pallidus. Less frequently, changes began before EMG activation: 20% of neurons in the putamen, 19% in caudate nucleus, and 17% in globus pallidus. In general, these changes in neuronal activity lasted longer than EMG activity associated with reaching. The proportions of neurons activated were significantly larger in the putamen than the caudate nucleus. In the pallidum, the proportions were not statistically different from either the putamen or caudate nucleus, and no significant difference was found between the internal and external pallidal segments. Significant selectivity for movements to different targets was observed in 36% of neurons in the putamen, 28% in the caudate nucleus and 9% in the globus pallidus. The lower proportion in the globus pallidus compared to the striatum was significant (P < 0.002). Clusters of activated neurons were found in the striatum, however, the timing of changes was often different for individual neurons in these clusters. A cross-correlation analysis of the activity of neurons in the clusters revealed no evidence of common inputs, suggesting that striatal neurons in close proximity with neurons showing similar changes in activity are driven by different populations of neurons. In the putamen, the anatomical locations of neurons with changes in activity related to movement execution were on average significantly more posterior and lateral than neurons with changes related to the preparation of movement described earlier [31]. These findings support the view that the putamen and the caudate nucleus contain distinct functional areas. The present studies show that most anatomical regions in both the striatum and palladum participate in the control of executing reaching movements.     

Calretinin-immunoreactive neurons in the human striatum

The human striatum contains two types of neurons displaying immunoreactivity for the calcium-binding protein calretinin (CR): (1) large (22–44 μm), multipolar neurons with 5–7 long, aspiny and highly branched dendrites, and (2) medium-sized (9–18 μm), round-to-oval neurons with 2–3 long, varicose and poorly branched dendrites. These CR neurons represent only a small proportion of the total neuronal population and they are heterogeneously distributed in the striatum. The large CR neurons are more numerous in the putamen than in the caudate nucleus, whereas the inverse is true for the medium-sized CR neurons. The ratio of large- to medium-sized CR neurons is 1:4 in the putamen compared to 1:16 in the caudate nucleus. The existence of these two distinct subsets of chemospecific striatal neurons suggest that CR may play an important role in the intrinsic organization of the human striatum.     

Reduced density of cholinergic interneurons in the ventral striatum in schizophrenia: an in situ hybridization study.

BACKGROUND: The role of the striatum in the pathophysiology of schizophrenia is not understood. In a previous postmortem study, we found a reduction in the density of striatal interneurons that stain immunohistochemically for choline acetyltransferase (ChAT) in schizophrenia. METHODS: To determine whether this finding represents a specific alteration in ChAT gene expression, we used in situ hybridization to study the striatum of 11 control and 9 schizophrenic subjects with oligonucleotide probes complementary to human ChAT mRNA, preprosomatostatin (PPS) mRNA, and beta-actin mRNA. Densities of ChAT mRNA-positive neurons, ChAT mRNA expression per neuron, PPS mRNA-positive neurons, and beta-actin mRNA expression levels were measured. RESULTS: There were no significant differences between the two groups in densities of PPS mRNA-positive neurons and levels of beta-actin mRNA expression throughout the striatum, or in densities of ChAT mRNA-positive neurons in the caudate nucleus or putamen. However, in the ventral striatum, the mean density of ChAT mRNA-positive neurons was reduced to 26% of control levels in the schizophrenic group. CONCLUSIONS: There is a reduction in number or function of the cholinergic interneurons of the ventral striatum in schizophrenia.     

Chemical architecture of the posterior striatum in the human brain

Summary. The neurochemical organization of the posterior caudate nucleus (CN) (body, gyrus and tail) and putamen (Put) was analyzed in the human brain using adjacent sections stained for acetylcholinesterase (AChE), limbic system-associated membrane protein (LAMP), enkephalin (ENK), parvalbumin (PV), calbindin (CB) and tyrosine hydroxylase (TH). Striosomes were visualized in all striatal regions but the anterior two thirds of the CN tail. They were highly immunoreactive (-ir) for ENK and LAMP, devoid of PV and AChE staining, and surrounded by a ring of tissue with pale TH- and CB-ir neuropil. In the Put, other rings of tissue completely free of ENK labeling surrounded certain striosomes (clear septa). In the CN body, gyrus and tail some markers revealed gradients and heterogeneities along the dorsoventral and mediolateral axes. A rim of striatal tissue densely stained for ENK and LAMP and poorly labeled for PV was noticeable along the lateral edge of the Put and the dorsolateral sector of the CN body. Our results illustrate a chemical architecture in the posterior striatum that is heterogeneous and slightly different from that found in the more anterior striatum. Correspondence: José Manuel Giménez-Amaya, Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina, Universidad Autónoma de Madrid, Despacho A-39, 28029 Madrid, Spain     

Aminooxyacetic acid produces excitotoxic lesions in the rat striatum.

The neuropathological, biochemical, and behavioral effects of intrastriatal injection of aminooxyacetic acid (AOAA), a non-specific transaminase inhibitor, were examined in rats. AOAA, 0.1-1 mumol, produced neuronal damage when injected into the striatum of adult rats but failed to damage the striatum of 6-d-old or decorticated rats. AOAA-induced (0.25 mumol-1 mumol) striatal lesions in adult rats displayed excitotoxic characteristics and could be prevented by the N-methyl-D-aspartate (NMDA) receptor antagonists (-)-2-amino-7-phosphono-heptanoate (AP7; 0.25 mumol) or kynurenate (KYNA; 0.5 mumol), but not by the non-NMDA antagonist 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo(F)quinoxaline (NBQX; 0.25 mumol). AOAA produced a dose-dependent reduction in striatal L-glutamate decarboxylase activity, as measured 14 d following intrastriatal injection, which could also be prevented by AP7 or KYNA, but not by NBQX. These findings suggest that AOAA-induced lesions are preferentially mediated by activation of the NMDA subtype of excitatory amino acid receptors. Behavioral studies revealed that the cataleptic response to haloperidol, 2 mg/kg, was decreased whereas the cataleptic response to arecoline, 15 mg/kg, and morphine, 15 mg/kg, was potentiated in AOAA lesioned animals 14 d following bilateral intrastriatal injections of AOAA, 0.25 and 1 mumol. In rats which received unilateral intrastriatal injection of AOAA, 0.1-1 mumol, apomorphine, 0.5 mg/kg, induced circling towards the lesioned side. Rats which received AP7, 0.25 mumol, or KYNA, 0.5 mumol, coadministered with AOAA, 0.25 mumol, behaved as vehicle-treated controls, while those which received NBQX, 0.25 mumol, and AOAA, 0.25 mumol, had behavioral patterns similar to those subjected to AOAA alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

The striatum and motor cortex in motor initiation and execution

The participation of striatal and motor cortex neurons in motor initiation and execution was studied using single neuronal recording in 3 monkeys performing wrist flexion and extension stimulus-initiated reaction time tasks. Observations of 46 striatal neurons whose activity correlated with the tasks were compared to recordings of 59 task-related motor cortex neurons. Neurons were classified as best related to the appearance of the go signal, movement onset, agonist or antagonist electromyographic changes, or the movement reaching target. Timing of neuronal activity changes in both striatum and motor cortex suggested that go signal-related neurons represent input function while most movement onset-related neurons represent output function. In the striatum, those related to reaching target represent output function. Furthermore, go signal-related neurons usually change activity before movement onset-related neurons which change activity prior to target attainment-related neurons. These observations suggest a hierarchical organization within the striatum and motor cortex. Also the striatum participates in programming target acquisition as well as motor initiation.     

Atrophy of medium spiny I striatal dendrites in advanced Parkinson's disease

Loss of dopaminergic neurons from the pars compacta of the substantia nigra is the pathological hallmark of Parkinson's disease (PD) and results in a partial deafferentation to the striatum. Since deafferentation is known to induce transynaptic atrophy of postsynaptic cells, we examined by Golgi impregnation the morphology of medium spiny I (MSI) striatal neurons, the principal target population for both nigrostriatal and corticostriatal fibers. Our quantitative data indicate that the dendritic arbor of MSI neurons in the putamen is significantly reduced in both length and number and MSI neurons are morphologically characterized by truncated dendrites with few dendritic spines and irregular, bulbous swellings. These data provide morphological evidence for the atrophy of striatal dendrites in PD and may explain, in part, the declining efficacy of chronicl-DOPA replacement therapy in advanced PD.     

Subcortical nuclei volumetry in idiopathic generalized epilepsy

PURPOSE: The exact anatomic and neurophysiologic correlates of idiopathic generalized epilepsy (IGE) in humans are still not well understood, although the thalamus has frequently been invoked as the crucial structure in the generation of primary generalized seizures. The few in vivo magnetic resonance (MR)-based studies in IGE patients suggest an altered cortical/subcortical gray matter ratio, but with no evidence of structural alterations of the thalamus. In this study, we sought to determine the volumes of the other subcortical structures. METHODS: The volumes of the caudate nucleus, putamen, pallidum as well as the thalamus were each determined in both hemispheres in 11 patients with various IGE syndromes, normalized for whole-brain volumes and then compared with 15 age-matched controls. RESULTS: No differences were noted in thalamic volumes, confirming previous reports. However, smaller subcortical volumes were noted in the IGE patients (p < 0.009), mainly due to smaller putamen bilaterally (p < or = 0.015). CONCLUSIONS: It is speculated that the presence of discrete frontal dysfunction, as noted in neuropsychological studies in IGE patients, indirectly supports our results because the putamen projects predominantly to the frontal cortex. Larger studies with more homogeneous patient populations are needed to determine the robustness of these findings and whether they are specific for particular IGE syndromes.     

Organization of dopamine D1 and D2 receptors in human striatum: receptor autoradiographic studies in Huntington's disease and schizophrenia

The technique of quantitative autoradiography was used to examine the effects of Huntington's disease (HD) and schizophrenia on the organization of striatal dopamine (DA) D1 and D2 receptors. Whereas the striatum of HD cases showed a reduction in the density of D1 ([3H]SCH 23390) and D2 ([3H]spiroperidol) receptors, the patterning of D2 receptor loss did not match that of the D1 receptor loss. The HD loss of D1 D1 receptors (65%) is far greater than the loss of D2 receptors (28%). Whereas there was a dorsal-ventral gradient of effect on both receptor subtypes, the effects of HD on D2 receptors in the ventral putamen (PUT) and nucleus accumben septi (NAS) were minimal. Similarly, muscarinic M1 and M2 receptors demonstrate different patterns of alteration in HD. The M2 subtype, labeled with [3H]N-methylscopolamine (in the presence of excess pirenzepine to occlude M1 sites), was depleted far more than the M1 receptor subtype, labeled with [3H]pirenzepine. Although the effects of HD on [3H]mazindol labeling of DA terminals were more heterogeneous, there appeared to be a relative preservation of this afferent input to the striatum of the HD cases. In the schizophrenic cases, our autoradiographic studies confirm previous reports of an elevation of D2 receptor density in the striata of many schizophrenics. This increase was evident even though two of the three cases were known to have not been treated with neuroleptics, and the third case may also have been drug naive. However, the increase was far greater in the NAS (164%) and ventral PUT (173%) than more dorsally in the striatum (68%). The density of D1 receptors and DA terminals labeled with [3H]mazindol in the striatum of schizophrenics was not significantly different from that of control cases. Thus in both HD and schizophrenia, the ratio of D2/D1 receptors is altered in favor of the D2 population, particularly in the NAS.     

Involvement of cytokines in human immunodeficiency virus-1 protein Tat and methamphetamine interactions in the striatum

Human immunodeficiency virus-1 (HIV-1) infection of the brain causes elevation in pro-inflammatory cytokines and inflammatory changes in the striatum. HIV-1-infected individuals who also abuse drugs including the psychostimulant methamphetamine (MA) develop more severe encephalitis and neuronal damage compared to HIV-1-infected patients who do not abuse drugs. In previous studies, we demonstrated that the HIV-1 protein Tat and MA interacted to cause enhanced loss of dopamine in the rat striatum via the destruction of dopaminergic terminals. Since both Tat and MA activate glia and induce cytokine production, we investigated the role of cytokines in the synergistic neurotoxicity induced by Tat and MA using cytokine arrays. Significant increases in monocyte chemotactic protein (MCP-1), interleukin-1 alpha (IL-1alpha) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels were noted 4 h following Tat + MA treatment compared to saline, Tat or MA. MCP-1 and TIMP-1 levels remained elevated 16 h after Tat + MA compared to saline or MA but were not different from the Tat-treated group at this time point. Weak, but significant elevations in cytokine-induced neutrophil chemoattractant-3 (CINC-3), ciliary neurotrophic factor (CNTF) and macrophage inflammatory protein-3 alpha (MIP-3alpha) were also noted with Tat + MA. The interaction of Tat and MA was prevented in mice genetically deficient in MCP-1 with a consequent attenuation of Tat + MA neurotoxicity. Our findings suggest that HIV-1 infection with concurrent drug abuse might profoundly increase chemokine levels in the striatum resulting in enhanced damage to the dopaminergic system.     

Compartmental distribution of cytochrome oxidase in the striatum of the rat.

Endogenous cytochrome oxidase activity was investigated in the adult rat striatum at the light microscope level to see if it was distributed in accordance with the established striatal patch/matrix compartmentalisation. Striatal sections stained to visualise cytochrome oxidase activity were compared with serial sections stained to visualise tyrosine hydroxylase and calbindinD28k-like immunoreactivity, established markers of the matrix compartment. The distribution of endogenous cytochrome oxidase activity was found to coincide with the immunocytochemical staining pattern seen for tyrosine hydroxylase and calbindinD28k whereby areas of intense tyrosine hydroxylase and calbindinD28k-like immunoreactivity (termed the matrix) corresponded to areas of intense cytochrome oxidase activity. Conversely, areas of less intense tyrosine hydroxylase and calbindinD28k-like immunoreactivity (termed patches) corresponded to areas of low cytochrome oxidase activity. In addition, the distribution of two other oxidative enzymes involved in the regulation of mitochondrial respiration, succinic dehydrogenase and NADH-diaphorase, was examined in the striatum and substantia nigra by using histochemical techniques. Both NADH-diaphorase and succinic dehydrogenase histochemistry showed an uneven pattern of neuropil staining in the striatum. In the substantia nigra a few intensely stained cell bodies were seen in the dorsal-lateral tip of the pars reticulata with both histochemical techniques. By using an anti-cytochrome oxidase antibody an abundance of immunoreactive cell bodies and processes were seen in the substantia nigra, particularly in the dorso-medial rim and dorsal tip of the pars reticulata. The substantia nigra pars lateralis contained many intensely stained cytochrome oxidase-like immunoreactive cell bodies and processes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sensorimotor deficits in a unilateral intrastriatal 6-OHDA partial lesion model of Parkinson's disease in marmoset monkeys

Animal studies investigating the efficacy of neurotrophic factors as treatments for Parkinson's disease (PD) ideally require partial dopamine (DA) lesion models. The intrastriatal 6-hydroxydopamine (6-OHDA) lesion model may be suitable for this purpose. Although this model has been well characterized in rodents, it has not previously been used in monkeys. The goal of the present study was to characterize the behavioral effects of unilateral injections of 6-OHDA in the basal ganglia of common marmoset monkeys (Callithrix jacchus). Cell counts from tyrosine hydroxylase immunochemistry 5 months postlesion revealed DA cell loss in the substantia nigra on the lesioned side to approximately 46% of relative to the unlesioned side. 6-OHDA lesioned monkeys showed a variety of behavioral deficits. Apomorphine induced rotation and simple sensorimotor measures (head position bias and PD disability rating score) were most affected by the lesion. The largest deficits were seen at 1 or 2 weeks postsurgery but had recovered by week 10. 6-OHDA lesioned monkeys took longer to complete a more complex sensorimotor staircase task. At 3.5 months postlesion, 6-OHDA monkeys also showed deficits on an object retrieval task designed to measure sensorimotor planning and skilled hand use. alpha-Methyl-p-tyrosine, a tyrosine hydroxylase inhibitor, reinstated those deficits which had undergone recovery in the lesioned animals and also exacerbated the deficits on the staircase task. This model has potential in assessing treatments for PD aimed at curtailing disease progression such as continuous delivery of neurotrophic factors.     

Selective reinforcement learning deficits in schizophrenia support predictions from computational models of striatal-cortical dysfunction.

BACKGROUND: Rewards and punishments may make distinct contributions to learning via separate striatal-cortical pathways. We investigated whether fronto-striatal dysfunction in schizophrenia (SZ) is characterized by selective impairment in either reward- (Go) or punishment-driven (NoGo) learning. METHODS: We administered two versions of a probabilistic selection task to 40 schizophrenia patients and 31 control subjects, using difficult to verbalize stimuli (experiment 1) and nameable objects (experiment 2). In an acquisition phase, participants learned to choose between three different stimulus pairs (AB, CD, EF) presented in random order, based on probabilistic feedback (80%, 70%, 60%). We used analyses of variance (ANOVAs) to assess the effects of group and reinforcement probability on two measures of contingency learning. To characterize the preference of subjects for choosing the most rewarded stimulus and avoiding the most punished stimulus, we subsequently tested participants with novel pairs of stimuli involving either A or B, providing no feedback. RESULTS: Control subjects demonstrated superior performance during the first 40 acquisition trials in each of the 80% and 70% conditions versus the 60% condition; patients showed similarly impaired (<60%) performance in all three conditions. In novel test pairs, patients showed decreased preference for the most rewarded stimulus (A; t = 2.674; p = .01). Patients were unimpaired at avoiding the most negative stimulus (B; t = .737). CONCLUSIONS: The results of these experiments provide additional evidence for the presence of deficits in reinforcement learning in SZ, suggesting that reward-driven learning may be more profoundly impaired than punishment-driven learning.