Szabolcs Kéri

The Effect of Dopamine Agonists on Adaptive and Aberrant Salience in Parkinson's Disease

Clinical evidence suggests that after initiation of dopaminergic medications some patients with Parkinsons disease (PD) develop psychotic symptoms, such as hallucinations and delusions. Here, we tested the hypothesis that the neurocognitive basis of this phenomenon can be defined as the formation of arbitrary and illusory associations between conditioned stimuli and reward signals, called aberrant salience. Young, never-medicated PD patients and matched controls were assessed on a speeded reaction time task in which the probe stimulus was preceded by conditioned stimuli that could signal monetary reward by color or shape. The patients and controls were re-evaluated after 12 weeks during which the patients received a dopamine agonist (pramipexole or ropinirole). Results indicated that dopamine agonists increased both adaptive and aberrant salience in PD patients, that is, formation of real and illusory associations between conditioned stimuli and reward, respectively. This effect was present when associations were assessed by means of faster responding after conditioned stimuli signaling reward (implicit salience) and overt rating of stimulus–reward links (explicit salience). However, unusual feelings and experiences, which are subclinical manifestations of psychotic-like symptoms, were specifically related to irrelevant and illusory stimulus–reward associations (aberrant salience) in PD patients receiving dopamine agonists. The learning of relevant and real stimulus–reward associations (adaptive salience) was not related to unusual experiences. These results suggest that dopamine agonists may increase psychotic-like experiences in young patients with PD, possibly by facilitating dopaminergic transmission in the ventral striatum, which results in aberrant associations between conditioned stimuli and reward.

Individuals With Posttraumatic Stress Disorder Show a Selective Deficit in Generalization of Associative Learning

OBJECTIVEnDrawing on two different populations, Israeli police and Hungarian civilians, the present study assessed the ability of individuals with posttraumatic stress disorder (PTSD) to generalize previous learning to novel situations. Past neuroimaging studies have demonstrated diminished medial temporal lobe (MTL) activation and/or reduced hippocampal volume in individuals with PTSD. Our earlier computational models of cortico-hippocampal function and subsequent experimental tests of these models in MTL-impaired clinical populations argue that even mild hippocampal dysfunction may result in subtle impairments in generalization. Therefore, we predicted that individuals with PTSD would show impaired generalization.nnnMETHODnWe compared the performance of five groups from two countries, including 19 Israeli police with PTSD and 22 trauma-exposed police without PTSD, and 22 Hungarian civilians with PTSD, 25 trauma-exposed civilians without PTSD, and 25 individuals without PTSD unexposed to the same trauma. Participants were tested on a two-phase learning paradigm, the Acquired Equivalence Task, which measures the ability to generalize past learning to novel situations.nnnRESULTSnWe found that both PTSD and non-PTSD participants were capable of learning the initial stimulus-outcome associations, F(4, 108) = 1.79, p = .14. However, as predicted, only individuals with PTSD showed a selective deficit in generalization of this learning to novel situations (F(4, 108) = 8.35, p < .001, Partial η2 = 0.26).nnnCONCLUSIONSnIndividuals with PTSD show a selective impairment in generalization of past learning similar to other clinical populations with MTL/hippocampal dysfunction. This is consistent with an emerging view of PTSD as being not only an anxiety disorder but also a learning disorder.

Why is vision impaired in fragile X premutation carriers? The role of fragile X mental retardation protein and potential FMR1 mRNA toxicity

Dysfunctions of the geniculo-striatal magnocellular (M) visual pathway and its cortical recipients have been documented in fragile X syndrome and in FMR1 premutation carriers. However, the mechanism of this impairment is less clear. To elucidate this issue, we completed the measurement of visual functions at different stages of information processing: low-level mechanisms (contrast sensitivity biasing information processing toward the M and parvocellular [P] pathways), primary visual cortex (motion-defined and static Vernier threshold), and higher-level form and motion processing (coherence thresholds). Results revealed that FMR1 premutation carriers, relative to non-carrier controls, exhibited lower contrast sensitivity for M pathway-biased stimuli, higher Vernier threshold for motion-defined stimuli, and higher global motion coherence threshold. Although both elevated FMR1 mRNA and reduced fragile X mental retardation protein (FMRP) levels were associated with impaired visual functions, regression analysis indicated that FMRP was the primary factor. In premutation carriers, a toxic gain-of-function of elevated FMR1 mRNA has been suggested, whereas reduced FMRP is linked to neurodevelopmental aspects. Here, we showed that FMRP may the primary factor associated with visual dysfunctions.

Hippocampal volume and the AKT signaling system in first-episode schizophrenia

OBJECTIVEnThe phosphoinositide 3-kinase (PI3K)--protein kinase B (AKT1)--glycogen synthase kinase (GSK)-3β system is modulated by several factors implicated in the pathophysiology of schizophrenia. Evidence suggests that neuregulin 1 (NRG1) induces decreased AKT phosphorylation in schizophrenia relative to healthy controls, which may be related to dysfunctional neurodevelopment and neuroplasticity. The aim of this study was to investigate the relationship between NRG1--induced AKT phosphorylation and hippocampal volume in schizophrenia.nnnMETHODSnParticipants were 20 first-episode patients with schizophrenia who did not receive psychotropic medications and 20 matched healthy controls. We measured the phosphorylated AKT--total AKT and phosphorylated ERK (extracellular signal-regulated kinase)--total ERK ratios in peripheral lymphoblasts before and after NRG1 administration. Whole-brain, left, and right hippocampal volumes were quantified using FreeSurfer software.nnnRESULTSnPatients with schizophrenia displayed decreased AKT but normal ERK ratio compared with controls. Patients also had a reduction in left hippocampal volume. There was no significant difference between patients and controls in whole-brain and right hippocampal volume. Decreased AKT ratio was associated with reduced hippocampal volume. There was no significant relationship between ERK ratio and brain structure.nnnCONCLUSIONnActivation of the AKT system is specifically associated with hippocampal volume in first-episode schizophrenia, which provides further evidence for the pivotal role of this messenger system in the pathophysiology of psychotic disorders.

How does the hippocampal formation mediate memory for stimuli processed by the magnocellular and parvocellular visual pathways? Evidence from the comparison of schizophrenia and amnestic mild cognitive impairment (aMCI)

Paired associates learning is impaired in both schizophrenia and amnestic mild cognitive impairment (aMCI), which may reflect hippocampal pathology. In addition, schizophrenia is characterized by the dysfunction of the retino-geniculo-striatal magnocellular (M) visual pathway. The purpose of this study was to investigate the interaction between visual perceptual and memory dysfunctions. We administered a modified version of the CANTAB paired associates learning task to patients with schizophrenia (n=20), aMCI (n=20), and two groups of matched healthy controls (n=20 for each patient group). The stimuli in the paired associates learning task biased information processing toward the M pathways (low contrast, low spatial frequency) and parvocellular (P) pathways (high contrast, high spatial frequency). Results revealed that patients with schizophrenia exhibited a more pronounced learning deficit for M-biased relative to P-biased stimuli. In aMCI, there were similar memory deficits for both types of stimuli. Orientation discrimination for M- and P-biased stimuli was intact in both groups of patients. The number of errors in the M-biased memory condition significantly and inversely correlated with the volume of the right hippocampus in schizophrenia. These results suggest an interaction between M-biased perceptual processing and short-term relational memory in schizophrenia, which may be associated with the structural alteration of the right hippocampus.

Impaired Generalization of Associative Learning in Patients with Alcohol Dependence After Intermediate-term Abstinence

AIMSnWe used an associative learning task in order to investigate cognitive dysfunctions in alcohol dependence. This test is suitable for the assessment of stimulus-response learning and memory generalization (acquired equivalence), which is related to medial temporal lobe functioning.nnnMETHODSnTwenty patients with alcohol dependence (abstinence: >6 months) and 20 matched healthy controls participated in the study. In the task, antecedent stimuli were cartoon faces (girl, boy, man and woman) and consequent stimuli were color cartoon fishes. The task was to learn face-fish associations using feedback. In the transfer phase, the fish-face pairs were generalized to new associations.nnnRESULTSnThere was no significant difference between patients and controls during the acquisition phase of fish-face associations. In the transfer phase, patients were impaired relative to controls. We found no association between task performance and intelligence quotient.nnnCONCLUSIONnThese results suggest that abstinent patients with alcohol dependence show marked dysfunctions in the generalization of associations, which may indicate the dysfunction of the medial temporal lobe.

Decreased peripheral expression of neuregulin 1 in high-risk individuals who later converted to psychosis.

Efforts to identify individuals with high psychosis risk have focused on biological markers that show a marked association with later conversion to full-blown psychosis. Hall et al. (2006) found that a variant in the human neuregulin 1 (NRG1) promoter region is associated with increased development of psychotic symptoms in high-risk individuals. These results were replicated in a Hungarian sample (Kéri et al., 2009). NRG1 plays an important role in neurodevelopment and synaptic plasticity by the regulation of glutamatergic and gamma-amynobutiric acidergic (GABAergic) neurons, and its risk variants are related to altered gene expression in postmortem brain tissue (Law et al., 2006). Previous studies demonstrated decreased peripheral NRG1expression in schizophrenia (Chagnon et al., 2008; Zhang et al., 2008), but it is not clear whether these changes can reliably predict psychosis conversion in high-risk individuals. In order to elucidate this issue, we enrolled 97 help-seeking individuals who visited the outpatient units of the University of Szeged, Bács-Kiskun Country Hospital, and Semmelweis University, Hungary. The control group included 50 healthy volunteers with a negative family history for psychotic disorders. Ultra-high-risk status was evaluated using the Comprehensive Assessment of At-Risk Mental States (CAARMS) (McGorry et al., 2003; for a study description, see Kéri et al., 2009). For the measurement of NRG1 isoforms, we adopted the protocol of Zhang et al. (2008). Blood was drawn from the cubital vein into a sterile plastic tube. Total RNA was extracted and reverse transcribed into first-strand cDNA. Two isoforms of NRG1 were measured using semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) (glial growth factor-2 [GGF2, type II] and heregulin beta 3 [HRG-beta3, type I]; upstream primer: 5′CTTTCTTGTTGCTGCATCTCC-3′; downstream primer: 5′-CACCCTTTTCAGGATGTGGT-3′). Glyceraldehyde-3-Phosphate Dehydrogenase (G3PDH) was the internal control because its level is unchanged in schizophrenia (upstream primer: 5′-ACCACAGTCCATGCCATCAC3′; downstream primer: 5′-TCCACCACCCTGTTGCTGTA-3′). We used cDNA for amplification with upstream and downstream primers of NRG1 and G3PDH, Taq DNA polymerase, dNTP, and PCR buffer. The protocol of the DNA thermal cycler included the following steps: initial denaturation at 95 °C for 5 min, cycles at 94 °C for 45 s, annealing at 65 °C (G3PDH at 62 °C) for 30 s, and extension at 72 °C for 90 s (35 cycles for NRG1 and 30 for G3PDH). Following the electrophoresis of the PCR products (2.0% agarose gel containing ethidium bromide), the optical density of NRG1 (type I and III combined) and G3PDH mRNA was determined. The ratio of the NRG1 and G3PDH mRNA optical density was the dependent measure (Zhang et al., 2008).

Falling out of time: enhanced memory for scenes presented at behaviorally irrelevant points in time in posttraumatic stress disorder (PTSD).

Spontaneous encoding of the visual environment depends on the behavioral relevance of the task performed simultaneously. If participants identify target letters or auditory tones while viewing a series of briefly presented natural and urban scenes, they demonstrate effective scene recognition only when a target, but not a behaviorally irrelevant distractor, appears together with the scene. Here, we show that individuals with posttraumatic stress disorder (PTSD), who witnessed the red sludge disaster in Hungary, show the opposite pattern of performance: enhanced recognition of scenes presented together with distractors and deficient recognition of scenes presented with targets. The recognition of trauma-related and neutral scenes was not different in individuals with PTSD. We found a positive correlation between memory for scenes presented with auditory distractors and re-experiencing symptoms (memory intrusions and flashbacks). These results suggest that abnormal encoding of visual scenes at behaviorally irrelevant events might be associated with intrusive experiences by disrupting the flow of time.

Emotion appraisal and the tryptophan hydroxylase 2 (TPH2) gene

The purpose of this study was to investigate the association between the G-703T polymorphism of the tryptophan hydroxylase 2 (TPH2) gene (rs4570625) and emotion appraisal in healthy volunteers. Participants were asked to recall a situation characterized by a strong emotion and to rate appraisal processes: novelty/expectation, pleasantness, goal-conduciveness, fairness, responsibility/causation, coping ability, morality, and relationship to self-concept. Results revealed that in the case of fear- and sadness-related autobiographical memories, participants with the GG genotype achieved higher appraisal scores for goal-conduciveness and lower scores for coping ability compared with participants with the TT genotype. In the case of joy, no differences were observed across genotypes. These results suggest that the TPH2 polymorphism affects appraisal processes in the case of negative emotions.