Rebbekah Atkinson

Duration mismatch negativity and P3a in first-episode psychosis and individuals at ultra-high risk of psychosis.

BACKGROUND Reduction in a pre-attentive measure of auditory change detection, mismatch negativity (MMN), is one of the most consistent findings in schizophrenia. Recently, our group showed a reduction in MMN to changes in the duration and intensity of background sounds in those within 5 years of illness onset, whereas reduced MMNs to changes in sound frequency were only seen in patients with longer illness duration. In this report, we examine whether reduced MMN, as well as P3a, another index of auditory deviance detection, to duration changes is evident even earlier in the illness, that is, in individuals in the first episode of a psychosis (FEP) and individuals identified as being at ultra-high risk of developing schizophrenia (UHR). METHODS Mismatch negativity and P3a were measured in 30 UHR individuals, 10 FEP individuals, and 20 healthy control subjects to both long (100 msec) and short (50 msec) duration deviant sounds. RESULTS Mismatch negativity was reduced to both duration deviants not only in the FEP group but also in the UHR group. P3a amplitude was also reduced in the UHR group but at trend level only in FEP. However, MMN and P3a reductions were unrelated in both UHR and FEP groups, suggesting that they reflect distinct deficits. CONCLUSIONS These results suggest that MMN, as well as P3a, to duration deviants are reduced in very early stages of a psychotic illness including those in an at-risk mental state. Both should be considered as potential markers of the prodrome.

Maturational changes in the subunit composition of AMPA receptors and the functional consequences of their activation in chicken forebrain.

AMPA receptors play a critical role in synaptic plasticity and brain development. Here we show that Ca2+ uptake in response to AMPA receptor activation decreases dramatically during maturation in chicken brain microslices without a change in tissue AMPA receptor content. We found that during maturation the relative concentration of GluR2 subunits increased, the concentration of the AMPA receptor-associated scaffold proteins SAP97 and GRIP decreased and that depolarization increased GluR1 phosphorylation at Ser831 in subcellular fractions enriched in postsynaptic densities at 2 weeks but not at 10 weeks. These changes are all consistent with a decreased Ca2+ entry through AMPA receptor channels in response to receptor activation and may account for the changes in the functional properties of the receptor, which are thought to underlie, at least in part, the physiological changes that occur with maturation.

Pre-pulse inhibition and antisaccade performance indicate impaired attention modulation of cognitive inhibition in 22q11.2 deletion syndrome (22q11DS)

Background22q11.2 deletion syndrome (22q11DS) is associated with a number of physical anomalies and neuropsychological deficits including impairments in executive and sensorimotor function. It is estimated that 25% of children with 22q11DS will develop schizophrenia and other psychotic disorders later in life. Evidence of genetic transmission of information processing deficits in schizophrenia suggests performance in 22q11DS individuals will enhance understanding of the neurobiological and genetic substrates associated with information processing. In this report, we examine information processing in 22q11DS using measures of startle eyeblink modification and antisaccade inhibition to explore similarities with schizophrenia and associations with neurocognitive performance.MethodsStartle modification (passive and active tasks; 120- and 480-ms pre-pulse intervals) and antisaccade inhibition were measured in 25 individuals with genetically confirmed 22q11DS and 30 healthy control subjects.ResultsIndividuals with 22q11DS exhibited increased antisaccade error as well as some evidence (trend-level effect) of impaired sensorimotor gating during the active condition, suggesting a dysfunction in controlled attentional processing, rather than a pre-attentive dysfunction using this paradigm.ConclusionsThe findings from the present study show similarities with previous studies in clinical populations associated with 22q11DS such as schizophrenia that may indicate shared dysfunction of inhibition pathways in these groups.

Electrophysiological, cognitive and clinical profiles of at-risk mental state: the longitudinal Minds in Transition (MinT) study

The onset of schizophrenia is typically preceded by a prodromal period lasting several years during which sub-threshold symptoms may be identified retrospectively. Clinical interviews are currently used to identify individuals who have an ultra-high risk (UHR) of developing a psychotic illness with a view to provision of interventions that prevent, delay or reduce severity of future mental health issues. The utility of bio-markers as an adjunct in the identification of UHR individuals is not yet established. Several event-related potential measures, especially mismatch-negativity (MMN), have been identified as potential biomarkers for schizophrenia. In this 12-month longitudinal study, demographic, clinical and neuropsychological data were acquired from 102 anti-psychotic naive UHR and 61 healthy controls, of whom 80 UHR and 58 controls provided valid EEG data during a passive auditory task at baseline. Despite widespread differences between UHR and controls on demographic, clinical and neuropsychological measures, MMN and P3a did not differ between these groups. Of 67 UHR at the 12-month follow-up, 7 (10%) had transitioned to a psychotic illness. The statistical power to detect differences between those who did or did not transition was limited by the lower than expected transition rate. ERPs did not predict transition, with trends in the opposite direction to that predicted. In exploratory analysis, the strongest predictors of transition were measures of verbal memory and subjective emotional disturbance.

Discriminative taste aversion learning: A learning task for older chickens

The study of learning and memory using the chicken model has relied on three learning paradigms, passive avoidance learning, imprinting and the pebble floor task. Passive avoidance learning and imprinting have been used predominantly in very young chickens and cannot be used to access learning and memory in older chickens. We have established a new behavioural learning paradigm, Discriminative Taste Aversion Learning (DTAL), that can be used with both young and older animals. The task requires chickens to discriminate between food crumbs dyed either red or yellow with one colour being associated with the aversive tasting substance, methylanthranilate. Learning can be tested at various times after the training session by presenting chickens with the coloured food crumbs without an aversive taste. Both chickens tested at 5 and 15 days post-hatch learned to avoid the aversive crumbs. Furthermore, the protein synthesis inhibitor anisomycin (30 mM; 10 microl per hemisphere) injected into the intermediate medial hyperstriatum ventrale 15 min pre-training or 45 min post-training blocked long-term memory for the DTAL task when tested 24 h later. Memory for the task was unaffected by anisomycin injection 120 min post-training or in control animals injected with saline at similar times. The timing of the cellular processes of protein synthesis needed for consolidation of the DTAL appears to be similar to those described for the other behavioural paradigms in young chickens.

Biochemical, behavioural and electrophysiological investigations of brain maturation in chickens.

It is convenient to divide the development of synaptic networks into two phases: synapse formation during which synaptic contacts are established, and a subsequent maturation phase during which synaptic circuits are fine tuned and the properties of individual synapses are modified. Understanding the complex factors that control the protracted maturation process in humans is likely to be important for understanding a variety of neurological and psychiatric disorders. Chickens provide an ideal experimental model in which maturation specific changes can be identified and the mechanisms controlling them can be elucidated because the maturation phase is protracted and temporally separated from the formation phase. This paper reviews the knowledge about the biological mechanisms involved in the maturation phase of brain development in chickens and presents some new data. Studies of synaptic physiology suggest that maturation may alter the basal set point for stimulus induced synaptic plasticity. Biochemical and pharmacological studies of N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and metabotropic glutamate receptors (mGluRs) revealed major changes in receptor regulation and the intracellular signalling pathways linked to receptor activation. Not surprisingly, therefore, when immature or mature chickens learn the same behavioural task the learning induced molecular events at the synapse are different. Changes in the features of auditory event related potentials and the basal EEG provide non-invasive techniques for monitoring maturation changes in chicken brain but prepulse inhibition (PPI) is too small and variable in chickens to be useful. Experimentally induced mild late-onset hypothyroidism retards some aspects of brain maturation and may help identify some of the mechanisms controlling maturation.

Molecular changes in the intermediate medial mesopallium after a one trial avoidance learning in immature and mature chickens

Because brain maturation in chickens is protracted and occurs well after the major developmental period of synaptogenesis, chicken forebrain is suitable to investigate whether the molecular mechanisms underlying memory consolidation are different in immature and mature animals. We have used antibodies and western blotting to analyze subcellular fractions from the intermediate medial mesopallium region of 14‐day and 8‐week chicken forebrain prepared 0, 45, and 120 min after learning a discriminative taste avoidance task. At both ages learning induced changes in the phosphorylation of the glutamate receptor subunit 1 at Ser831, the levels of calcium‐calmodulin stimulated/dependent protein kinase II and the phosphorylation of calcium‐calmodulin stimulated/dependent protein kinase II at Thr286 were observed only in the fraction enriched in post‐synaptic densities. The changes were of the same type at the two ages but occurred faster in mature animals. The changes in extracellular signal regulated kinase and phosphorylated‐extracellular signal regulated kinase were more complex with different subcellular fractions showing different patterns of change at the two ages. These results imply that the molecular changes induced by learning a behavioral task are faster in mature than immature brain and may involve a different balance of intracellular signaling pathways.

Changes in mid‐to‐late latency auditory evoked reponses in the chicken during neural maturation

Utilizing the special advantages offered by the protracted maturation of neural circuits in chicken forebrain this study investigates the functional consequence of maturation using auditory evoked response potentials (AERPs) in behaving animals. Repeated measures AERP recordings were undertaken between weeks 1 and 8 posthatch. Quantitative analysis revealed a significant decrease in amplitude of the positive AERP component and a decrease in latency of the negative AERP component with maturation. AERPs were also utilized to investigate perturbed maturation via the induction of chemically induced hypothyroidism. Results from this study showed that the induction of late onset hypothyroidism produces measurable effects on the chicken AERP consistent with perturbation in maturation of neuronal circuits and synapses. This suggests that AERPs may be useful noninvasive functional measures of brain maturation that can be used to study the effects of endogenous or exogenous factors on brain maturation in the chicken. Since human brain also exhibits a protracted maturation period the availability of a well-characterized animal model for protracted brain maturation provides an opportunity to identify molecules, genes and environmental factors that are important in the regulation of maturation. The protracted maturation of neuronal circuits observed in chicken forebrain offers such a model.