Fractionated Radiation Exposure of Rat Spinal Cords Leads to Latent Neuro- Inflammation in Brain, Cognitive Deficits,and Alterations in Apurinic Endonuclease 1

Ionizing radiation causes degeneration of myelin, the insulating sheaths of neuronal axons, leading to neurological impairment. As radiation research on the central nervous system has predominantly focused on neurons, with few studies addressing the role of glial cells, we have focused our present research on identifying the latent effects of single/ fractionated -low dose of low/ high energy radiation on the role of base excision repair protein Apurinic Endonuclease-1, in the rat spinal cords oligodendrocyte progenitor cells’ differentiation. Apurinic endonuclease-1 is predominantly upregulated in response to oxidative stress by low- energy radiation, and previous studies show significant induction of Apurinic Endonuclease-1 in neurons and astrocytes. Our studies show for the first time, that fractionation of protons cause latent damage to spinal cord architecture while fractionation of HZE (28Si) induce increase in APE1 with single dose, which then decreased with fractionation. The oligodendrocyte progenitor cells differentiation was skewed with increase in immature oligodendrocytes and astrocytes, which likely cause the observed decrease in white matter, increased neuro-inflammation, together leading to the observed significant cognitive defects.

The differential effects of chlorpromazine and haloperidol on latent inhibition in healthy volunteers.

Latent inhibition (LI) is a measure of reduced learning about a stimulus to which there has been prior exposure without any consequence. It therefore requires a comparison between a pre-exposed (PE) and a non-pre-exposed (NPE) condition. Since, in animals, LI is disrupted by amphetamines and enhanced by antipsychotics, LI disruption has been proposed as a measure of the characteristic attentional deficit in schizophrenia: the inability to ignore irrelevant stimuli. The findings in humans are, however, inconsistent. In particular, a recent investigation suggested that since haloperidol disrupted LI in healthy volunteers, and LI was normal in non-medicated patients with schizophrenia, the previous findings in schizophrenic patients were entirely due to the negative effects of their medication on LI (Williams et al., 1998). We conducted two studies of antipsychotic drug effects on auditory LI using a within-subject, parallel group design in healthy volunteers. In the first of these, single doses of haloperidol (1 mg. i.v.) were compared with paroxetine (20 mg p.o.) and placebo, and in the second, chlorpromazine (100 mg p.o.) was compared with lorazepam (2 mg. p.o.) and placebo. Eye movements, neuropsychological test performance (spatial working memory (SWM), Tower of London and intra/extra dimensional shift, from the CANTAB test battery) and visual analogue rating scales, were also included as other measures of attention and frontal lobe function. Haloperidol was associated with a non-significant reduction in LI scores, and dysphoria/akathisia (Barnes Akathisia Rating Scale) in three-quarters of the subjects. The LI finding may be explained by increased distractibility which was indicated by an increase in antisaccade directional errors in this group. In contrast, LI was significantly increased by chlorpromazine but not by an equally sedative dose of lorazepam (both drugs causing marked decreases in peak saccadic velocity). Paroxetine had no effect on LI, eye movements or CANTAB neuropsychological test performance. Haloperidol was associated with impaired SWM, which correlated with the degree of dysphoria/akathisia, but no other drug effects on CANTAB measures were detected. We conclude that the effect of antipsychotics on LI is both modality and pharmacologically dependent and that further research using a wider range of antipsychotic compounds is necessary to clarify the cognitive effects of these drugs, and to determine whether there are important differences between them.

Differential effects of the CCKA receptor ligands PD-140, 548 and A-71623 on latent inhibition in the rat.

Latent inhibition (LI) is a behavioural paradigm in which repeated exposure to a stimulus without consequence inhibits the formation of any new associations with that stimulus. To the extent that LI reflects a process of learning to ignore irrelevant stimuli, disrupted LI has been suggested as an animal model for the attentional deficits observed in schizophrenia. The antipsychotic potential of cholecystokinin (CCK) stems from its colocalization with dopamine (DA) in the mesolimbic pathway, where it demonstrates both excitatory and inhibitory effects on dopaminergic activity. This may be explained by mediation through different receptor subtypes. A variety of hypotheses has emerged regarding the potential clinical application of subtype-selective CCK-based drugs. The present experiments examined the effects on LI of two selective CCKA ligands: PD-140,548 (a CCKA antagonist, Experiment 1: 0.001, 0.01, and 0.1 mg/kg) and A-71623 (a CCKA agonist, Experiment 2: 0.02, 0.05, and 0.1 mg/kg). In both experiments, the effects of haloperidol (0.1 mg/kg) were also investigated. Animals receiving 0.1 mg/kg of haloperidol or 0.001 or 0.1 mg/kg (but not 0.01 mg/kg) of PD-140,548 treated the preexposed stimulus as irrelevant after a low number of preexposures. In contrast, no facilitatory effect on LI was detectable at any of the A-71623 doses. The finding that A-71623 failed to enhance LI indicates that it is unlikely that this compound would have any antipsychotic effect within the clinical setting. Considering the facilitatory effect exerted by PD-140,548 on LI, it is probable that the inhibition of CCK activity might prove a more promising strategy for the pharmacological treatment of schizophrenia.

Normal levels of prepulse inhibition in the euthymic phase of bipolar disorder.

BACKGROUND:Deficits in prepulse inhibition (PPI) of the acoustic startle response have been suggested as a potentially useful endophenotype for schizophrenia spectrum disorders and may explain certain symptoms and cognitive deficits observed in the psychoses. PPI deficits have also been found in mania, but it remains to be confirmed whether this dysfunction is present in the euthymic phase of bipolar disorder.METHOD: Twenty-three adult patients with DSM-IV bipolar disorder were compared to 20 controls on tests of acoustic startle reactivity and PPI of the startle response. Sociodemographic and treatment variables were recorded and symptom scores assessed using the Hamilton Depression Inventory and the Young Mania Rating Scale.RESULTS:Overall, the patient and control groups demonstrated similar levels of startle reactivity and PPI, although there was a trend for the inter-stimulus interval to differentially affect levels of PPI in the two groups.CONCLUSIONS: In contrast to bipolar patients experiencing a manic episode, general levels of PPI were normal in this euthymic sample. Further studies are required to confirm this finding and to determine the mechanisms by which this potential disruption/normalization occurs. It is suggested that an examination of PPI in a high-risk group is required to fully discount dysfunctional PPI as a potentially useful endophenotype for bipolar disorder.

Exploring eye movement analysis as a measure of selective visual attention in brain injured individuals

Primary Objective: To investigate the utility of using a new method of assessment for deficits in selective visual attention (SVA). Methods and Procedures: An independent groups design compared six participants with brain injuries with six participants from a non-brain injured control group. The Sensomotoric Instruments Eye Movement system with remote eye-tracking device (eye camera), and 2 sets of eight stimuli were employed to determine if the camera would be a sensitive discriminator of SVA in these groups. Main Outcomes and Results: The attention profile displayed by the brain injured group showed that they were slower, made more errors, were less accurate, and more indecisive than the control group. Conclusions: The utility of eye movement analysis as an assessment method was established, with implications for rehabilitation requiring further development. Key words: selective visual attention, eye movement analysis, brain injury

North/South Infrastructure Development via Cross-border PPP Mechanism

Both Northern Ireland and Republic of Ireland governments recognise the current infrastructural deficits in their respective jurisdictions which, if not addressed, will undermine the future economic prosperity of both regions. This paper considers the adoption of a collaborative approach on the island to addressing the deficit, using public private partnerships (PPP) as the delivery vehicle. It presents a critical perspective of the challenges and opportunities posed by adopting such a cross-border approach. Whilst PPPs have the potential to bring about North-South co-operation, bridge gaps in infrastructure capacity and facilitate the advancement of sectoral knowledge, their adoption on a cross border basis will require significant reorganisation and change at administrative and sectoral levels. This review concludes that governments and construction sector representatives in Northern Ireland and the Republic of Ireland have still some work to do in order to enhance the capability and readiness of public and private partners to evolve an all-island PPP infrastructure development approach.

Errorless learning and memory performance in schizophrenia

There is evidence that patients with schizophrenia have impaired explicit memory and intact implicit memory. The present study sought to replicate and extend that of O'Carroll et al. [O'Carroll, R.E., Russell, H.H., Lawrie, S.M. and Johnstone, E.C., 1999. Errorless learning and the cognitive rehabilitation of memory-impaired schizophrenic patients. Psychological Medicine 29, 105-112.] which reported that for memory-impaired patients with schizophrenia performance on a (cued) word recall task is enhanced using errorless learning techniques (in which errors are prevented during learning) compared to errorful learning (the traditional trial-and-error approach). Thirty patients with a DSM-IV diagnosis of schizophrenia and fifteen healthy controls (HC) participated. The Rivermead Behavioural Memory Test was administered and from their scores, the schizophrenic patients were classified as either memory-impaired (MIS), or memory-unimpaired (MUS). During the training phase two lists of words were learned separately, one using the errorless learning approach and the other using an errorful approach. Subjects were then tested for their recall of the words using cued recall. After errorful learning training, performance on word recall for the MIS group was impaired compared to the MUS and HC groups. However, after errorless learning training, no significant differences in performance were found between the three groups. Errorless learning may play an important role in remediation of cognitive deficits for patients with schizophrenia. (c) 2007 Elsevier Ireland Ltd. All rights reserved.

Muscle coordination during rapid force production by young and older adults

Background. Older adults typically exhibit dramatic reductions in the rate of force development and deficits in the execution of rapid coordinated movements. The purpose of the current study was to investigate the association between the reduced rate of force development exhibited by older adults and the ability to coordinate groups of muscles.

Impaired conflict resolution and alerting in children with ADHD: evidence from the Attention Network Task (ANT)

An important theory of attention suggests that there are three separate networks that execute discrete cognitive functions. The 'alerting' network acquires and maintains an alert state, the 'orienting' network selects information from sensory input and the 'conflict' network resolves conflict that arises between potential responses. This theory holds promise for dissociating discrete patterns of cognitive impairment in disorders where attentional deficits may often be subtle, such as in attention deficit hyperactivity disorder (ADHD).

Dissociation in performance of children with ADHD and high-functioning autism on a task of sustained attention

Attention deficit hyperactivity disorder (ADHD) and autism are two neurodevelopmental disorders associated with prominent executive dysfunction, which may be underpinned by disruption within fronto-striatal and fronto-parietal circuits. We probed executive function in these disorders using a sustained attention task with a validated brain-behaviour basis. Twenty-three children with ADHD, 21 children with high-functioning autism (HFA) and 18 control children were tested on the Sustained Attention to Response Task (SART). In a fixed sequence version of the task, children were required to withhold their response to a predictably occurring no-go target (3) in a 1-9 digit sequence; in the random version the sequence was unpredictable. The ADHD group showed clear deficits in response inhibition and sustained attention, through higher errors of commission and omission on both SART versions. The HFA group showed no sustained attention deficits, through a normal number of omission errors on both SART versions. The HFA group showed dissociation in response inhibition performance, as indexed by commission errors. On the Fixed SART, a normal number of errors was made, however when the stimuli were randomised, the HFA group made as many commission errors as the ADHD group. Greater slow-frequency variability in response time and a slowing in mean response time by the ADHD group suggested impaired arousal processes. The ADHD group showed greater fast-frequency variability in response time, indicative of impaired top-down control, relative to the HFA and control groups. These data imply involvement of fronto-parietal attentional networks and sub-cortical arousal systems in the pathology of ADHD and prefromal cortex dysfunction in children with HFA. (c) 2007 Elsevier Ltd. All rights reserved.

Movement-related potentials in Huntington's disease: movement preparation and execution

Movement-related potentials (MRPs) reflect increasing cortical activity related to the preparation and execution of voluntary movement. Execution and preparatory components may be separated by comparing MRPs recorded from actual and imagined movement. Imagined movement initiates preparatory processes, but not motor execution activity. MRPs are maximal over the supplementary motor area (SMA), an area of the cortex involved in the planning and preparation of movement. The SMA receives input from the basal ganglia, which are affected in Huntington's disease (HD), a hyperkinetic movement disorder. In order to further elucidate the effects of the disorder upon the cortical activity relating to movement, MRPs were recorded from ten HD patients, and ten age-matched controls, whilst they performed and imagined performing a sequential button-pressing task. HD patients produced MRPs of significantly reduced size both for performed and imagined movement. The component relating to movement execution was obtained by subtracting the MRP for imagined movement from the MRP for performed movement, and was found to be normal in HD. The movement preparation component was found by subtracting the MRP found for a control condition of watching the visual cues from the MRP for imagined movement. This preparation component in HD was reduced in early slope, peak amplitude, and post-peak slope. This study therefore reported abnormal MRPs in HD. particularly in terms of the components relating to movement preparation, and this finding may further explain the movement deficits reported in the disease.

Phonological oddballs in the focus of attention elicit a normal P3b in dyslexic adults

Difficulties in phonological processing have been proposed to be the core symptom of developmental dyslexia. Phoneme awareness tasks have been shown to both index and predict individual reading ability. In a previous experiment, we observed that dyslexic adults fail to display a P3a modulation for phonological deviants within an alliterated word stream when concentrating primarily on a lexical decision task [Fosker and Thierry, 2004, Neurosci. Lett. 357, 171-174]. Here we recorded the P3b oddball response elicited by initial phonemes within streams of alliterated words and pseudo-words when participants focussed directly on detecting the oddball phonemes. Despite significant verbal screening test differences between dyslexic adults and controls, the error rates, reactions times, and main components (P2, N2, P3a, and P3b) were indistinguishable across groups. The only difference between groups was found in the NI range, where dyslexic participants failed to show the modulations induced by phonological pairings (/b/-/p/ versus /r/ /g/) in controls. In light of previous P3a differences, these results suggest an important role for attention allocation in the manifestation of phonological deficits in developmental dyslexia. (c) 2005 Elsevier B.V. All rights reserved.

Imitation and 'theory of mind' competencies in discrimination of autism from other neurodevelopmental disorders

Several studies have reported imitative deficits in autism spectrum disorder (ASD). However, it is still debated if imitative deficits are specific to ASD or shared with clinical groups with similar mental impairment and motor difficulties. We investigated whether imitative tasks can be used to discriminate ASD children from typically developing children (TD) and children with general developmental delay (GDD). We applied discriminant function analyses to the performance of these groups on three imitation tasks and tests of dexterity, motor planning, verbal skills, theory of mind (ToM). Analyses revealed two significant dimensions. The first represented impairment of dexterity and verbal ability, and discriminated TD from GDD children. Once these differences were accounted for, differences in ToM and the three imitation tasks accounted for a significant proportion of the remaining intergroup variance and discriminated the ASD group from other groups. Further analyses revealed that inclusion of imitative tasks increased the specificity and sensitivity of ASD classification and that imitative tasks considered alone were able to reliably discriminate ASD, TD and GDD. The results suggest that imitation and theory of mind impairment in autism may stem from a common domain of origin separate from general cognitive and motor skill.

Effects of intrahippocampal NAC(61-95) injections on memory in the rat and attenuation with vitamin E

Parkinson's disease (PD)-related dementia affects approximately 40% of PD patients and the severity of this dementia correlates significantly with the density of Lewy body (LB) deposition in the PD brain. Aggregated alpha-synuclein protein is the major component of LB's and the non-amyloid component (NAC) region of alpha-synuclein, residues 61-95, is essential for the aggregation and toxicity of this protein. The current study evaluated the effect of pre-aggregated NAC(61-95) injected into the CA3 area of the dorsal hippocampus of the brain on memory in the rat. Previous research has suggested that oxidative stress processes may play a role in the neuropathology of PD, therefore the effect of treatment with vitamin E, an antioxidant, was also evaluated. Male Sprague-Dawley rats were trained in two-lever operant chambers under an alternating-lever cyclic-ratio (ALCR) schedule of food reinforcement. When responding showed no trends, subjects were divided into four groups. Two groups were injected bilaterally into the dorsal hippocampus with aggregated NAC(61-95) (5 mu l suspension), and two groups were injected bilaterally into the dorsal hippocampus with sterile water (5 mu l). Subgroups were treated with either vitamin E (150 mg/kg in Soya oil) or vehicle (Soya oil) daily. Injection of NAC(61-95) induced memory deficits and vitamin E treatment alleviated these. In addition, NAC(61-95) injections induced activated astrocytes and chronic treatment with vitamin E reduced the numbers of activated astrocytes. These results suggest that aggregated NAC(61-95) and associated oxidative stress, may play a role in the pathogenesis of cognitive deficits seen in PD-induced dementia. (C) 2009 Elsevier Inc. All rights reserved.