Reversal of schizophrenia-like symptoms and immune alterations in mice by immunomodulatory drugs

Immune dysregulation observed in schizophrenia alters tryptophan metabolism. Tryptophan metabolism is triggered by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Tryptophan is converted to quinolinic acid, a potent neurotoxin, and to kynurenic acid, an NMDA antagonist. 1-Methyl-D-tryptophan (MDT) inhibits IDO. Melatonin is metabolized by IDO while inhibiting TDO. We evaluated the reversal of ketamine-induced schizophrenia-like behavioral and neurochemical alterations in mice by the administration of MDT (20 or 40 mg/kg, i.p.) or melatonin (15 mg/kg, per os). Oxidative stress and inflammatory alterations, i.e. myeloperoxidase activity (MPO), reduced glutathione (GSH), lipid peroxidation (LPO) and interleukin (IL)-4 and IL-6 were measured in the prefrontal cortex (PFC), hippocampus and striatum. Risperidone was used as standard antipsychotic. Ketamine triggered positive- (PPI deficits and hyperlocomotion), cognitive- (working memory deficits) and negative (social interaction deficits) schizophrenia-like symptoms. These symptoms were accompanied by increased MPO activity, decreased GSH and increased LPO in all brain areas and increments in hippocampal IL-4 and IL-6. MDT and melatonin reversed all ketamine-induced behavioral alterations. Risperidone did not reverse working memory deficits. MDT and melatonin reversed alterations in MPO activity and GSH levels. LP was reversed only by melatonin and risperidone. Risperidone could not reverse MPO alterations in the PFC and striatum. All drugs reversed the alterations in IL-4 and IL-6. The hippocampus and striatum of ketamine+melatonin-treated animals had lower levels of IL-6. Our findings provide further preclinical evidence that immune-inflammatory and oxidative pathways are involved in schizophrenia and that targeting these pathways is a valid treatment option in schizophrenia.     

Impaired contrast sensitivity is associated with more severe cognitive impairment in Parkinson disease

ObjectivesDopaminergic degeneration affects both nigrostriatal projection neurons and retinal amacrine cells in Parkinson disease (PD). Parkinsonian retinopathy is associated with impaired color discrimination and contrast sensitivity. Some prior studies described associations between color discrimination deficits and cognitive deficits in PD, suggesting that contrast discrimination deficits are due, at least in part, to cognitive deficits in PD. We investigated the relationship between cognitive deficits and impaired contrast sensitivity in PD.MethodsPD subjects, n = 43; 15F/28M; mean age 66.5 ± 8.2, Hoehn and Yahr stage 2.6 ± 0.6, and duration of disease of 6.2 ± 5.0 years underwent neuropsychological and Rabin contrast sensitivity testing.ResultsMean Rabin contrast sensitivity score was 1.34 ± 0.40. Bivariate analyses showed significant correlation between Rabin contrast sensitivity scores and global cognitive z-scores (R = 0.54, P = 0.0002). Cognitive domain Z-score post hoc analysis demonstrated most robust correlation between Rabin scores and executive functions (R = 0.49, P = 0.0009), followed by verbal learning (R = 0.44, P = 0.0028), visuospatial (R = 0.39, P = 0.001) and attention z-scores (R = 0.32, P = 0.036).ConclusionsImpaired contrast sensitivity in PD is robustly associated with cognitive deficits, particularly executive function deficits. These results suggest that contrast sensitivity may be a useful biomarker for cognitive changes in PD and may have implications for driving safety evaluations in PD.     

Electrical mapping in bipolar disorder patients during the oddball paradigm

Bipolar disorder (BD) is characterized by an alternated occurrence between acute mania episodes and depression or remission moments. The objective of this study is to analyze the information processing changes in BP (Bipolar Patients) (euthymia, depression and mania) during the oddball paradigm, focusing on the P300 component, an electric potential of the cerebral cortex generated in response to external sensorial stimuli, which involves more complex neurophysiological processes related to stimulus interpretation. Twenty-eight bipolar disorder patients (BP) (17 women and 11 men with average age of 32.5, SD: 9.5) and eleven healthy controls (HC) (7 women and 4 men with average age of 29.78, SD: 6.89) were enrolled in this study. The bipolar patients were divided into 3 major groups (i.e., euthymic, depressive and maniac) according to the score on the Clinical Global Impression – Bipolar Version (CGI-BP). The subjects performed the oddball paradigm simultaneously to the EEG record. EEG data were also recorded before and after the execution of the task. A one-way ANOVA was applied to compare the P300 component among the groups. After observing P300 and the subcomponents P3a and P3b, a similarity of amplitude and latency between euthymic and depressive patients was observed, as well as small amplitude in the pre-frontal cortex and reduced P3a response. This can be evidence of impaired information processing, cognitive flexibility, working memory, executive functions and ability to shift the attention and processing to the target and away from distracting stimuli in BD. Such neuropsychological impairments are related to different BD symptoms, which should be known and considered, in order to develop effective clinical treatment strategies.     

Progression of small vessel disease correlates with cortical thinning in Parkinson’s disease

ObjectiveCerebral small-vessel disease (SVD) is a risk factor for dementia in Parkinson’s disease (PD), however the pathophysiological role of SVD in PD-dementia is unclear. We investigated the impact of baseline and progression of SVD on cortical thickness and the correlation to cognition.MethodsSeventy-three mild PD patients with baseline and follow-up structural MRI scans, serial clinical and neuropsychological assessments were studied. SVD included the load of white matter hyperintensities (WMH), lacunes and perivascular spaces (PVS). WMH progression was assessed using the modified Rotterdam Progression scale, while for lacunes and PVS, development of new lesions was considered as lesion progression. Patients were classified as having SVD-progression and SVD-no-progression based on the longitudinal changes in their SVD measures. Freesurfer was used to measure baseline and follow-up regional cortical thickness and subcortical volumes and correlated to cognitive performance.ResultsFourteen patients were classified as SVD-progression and 59 as SVD-no-progression. Over 18 months, PD SVD-progression demonstrated significant cortical thinning in the left frontal and bilateral parietal regions with associated decline in memory, executive function, and motor functions. PD SVD-progression also had reduced volumes in the nucleus accumbens and amygdala at baseline and greater atrophy in the caudate nucleus over 18 months.DiscussionThe extent and progression of SVD is associated with focal cerebral atrophy and domain-specific cognitive dysfunction. Measures to retard SVD may be potentially useful in preventing dementia in PD.     

A systematic review of mirror neuron system function in developmental coordination disorder: Imitation,motor imagery,and neuroimaging evidence

PURPOSEThe aim of this systematic review was to investigate the evidence of abnormal functioning of the mirror neuron system (MNS) in children and adults with developmental coordination disorder (DCD), through examination of imitation, motor imagery, and neuroimaging literature.METHODSThe following databases were comprehensively searched for relevant articles: CINAHL Plus, Embase, MEDLINE, PsycINFO, Pubmed, and Web of Science. Full-text articles of all potentially relevant citations were obtained and assessed for eligibility by two authors. Outcome measures of interest at a motor behaviour level were any measures of imitation or motor imagery proficiency and, at a neurological level, were any measures of neural activity in MNS brain regions. Due to differences in outcome measures between studies and the variables reported, a narrative review was undertaken to synthesise findings from the studies.RESULTSOverall, 31 articles met the inclusion criteria. Children and adults with DCD display deficits imitating meaningful and novel gestures and demonstrate different response patterns to controls when undertaking complex motor imagery tasks. Children with DCD present reduced activation and connectivity of frontal, parietal, and temporal MNS regions.CONCLUSIONSPreliminary evidence indicates some deficit in the functioning of the MNS at a motor behaviour and neurological level. As no published neuroimaging studies have been designed specifically to explore MNS function, these results must be interpreted with caution. Further research to explore the MNS hypothesis in greater detail, particularly from a neuroimaging perspective, has the potential to provide information on the underlying mechanisms of DCD, inform future research into the aetiology of this disorder, and inform intervention approaches.     

Spontaneous improvement in both obstructive sleep apnea and cognitive impairment after stroke

BackgroundKnowledge available about the relationship between obstructive sleep apnea (OSA) and cognitive impairment after stroke is limited. The evolution of OSA and cognitive performance after stroke is not sufficiently described.MethodsWe prospectively enrolled and examined acute stroke patients without previously diagnosed OSA. The following information was collected: (1) demographics, (2) sleep cardio-respiratory polygraphy (PG) at 72 h, day seven, month three, and month 12 after stroke, (3) post-stroke functional disability tests at entry and at months three and 12, and (4) cognition (attention and orientation, memory, verbal fluency, language, and visual-spatial abilities) using the revised Addenbrooke's Cognitive Examination (ACE-R) at months three and 12.ResultsOf 68 patients completing the study, OSA was diagnosed in 42 (61.8%) patients. The mean apnea/hypopnea index (AHI) at study entry of 21.0 ± 13.7 spontaneously declined to 11.6 ± 11.2 at month 12 in the OSA group (p < 0.0005). The total ACE-R score was significantly reduced at months three (p = 0.005) and 12 (p = 0.004) in the OSA group. Poorer performance on the subtests of memory at months 3 (p = 0.039) and 12 (p = 0.040) and verbal fluency at months 3 (p < 0.005) and 12 (p < 0.005) were observed in the OSA group compared to non-OSA group. Visual-spatial abilities in both the OSA (p = 0.001) and non-OSA (p = 0.046) groups and the total ACE-R score in the OSA (p = 0.005) and non-OSA (p = 0.002) groups improved.ConclusionsA high prevalence of OSA and cognitive decline were present in patients after an acute stroke. Spontaneous improvements in both OSA and cognitive impairment were observed.     

Clinical correlates of graph theory findings in temporal lobe epilepsy

PurposeTemporal lobe epilepsy (TLE) is considered a brain network disorder, additionally representing the most common form of pharmaco-resistant epilepsy in adults. There is increasing evidence that seizures in TLE arise from abnormal epileptogenic networks, which extend beyond the clinico-radiologically determined epileptogenic zone and may contribute to the failure rate of 30–50% following epilepsy surgery. Graph theory allows for a network-based representation of TLE brain networks using several neuroimaging and electrophysiologic modalities, and has potential to provide clinicians with clinically useful biomarkers for diagnostic and prognostic purposes.MethodsWe performed a review of the current state of graph theory findings in TLE as they pertain to localization of the epileptogenic zone, prediction of pre- and post-surgical seizure frequency and cognitive performance, and monitoring cognitive decline in TLE.ResultsAlthough different neuroimaging and electrophysiologic modalities have yielded occasionally conflicting results, several potential biomarkers have been characterized for identifying the epileptogenic zone, pre-/post-surgical seizure prediction, and assessing cognitive performance. For localization, graph theory measures of centrality have shown the most potential, including betweenness centrality, outdegree, and graph index complexity, whereas for prediction of seizure frequency, measures of synchronizability have shown the most potential. The utility of clustering coefficient and characteristic path length for assessing cognitive performance in TLE is also discussed.ConclusionsFuture studies integrating data from multiple modalities and testing predictive models are needed to clarify findings and develop graph theory for its clinical utility.     

Diffusion alterations associated with Parkinson's disease symptomatology: A review of the literature

Parkinson's disease (PD) is a heterogeneous neurological disorder with a variety of motor and non-motor symptoms. The underlying mechanisms of these symptoms are not fully understood. An increased interest in structural connectivity analyses using diffusion tensor imaging (DTI) in PD has led to an expansion of our understanding of the impact of abnormalities in diffusivity on phenotype. This review outlines the contribution of these abnormalities to symptoms of PD including bradykinesia, tremor and non-tremor phenotypes, freezing of gait, cognitive impairment, mood, sleep disturbances, visual hallucinations and olfactory dysfunction. Studies have shown that impairments in cognitive functioning are related to diffusion abnormalities in frontal and parietal regions, as well as in the corpus callosum and major fibres connecting midbrain and subcortical structures with the neocortex. However, the impact of diffusion alterations on motor, mood and other symptoms of PD are less well understood. The findings presented here highlight the challenges faced and the potential areas of future research avenues where DTI may be beneficial. Larger cohort studies and standardized imaging protocols are required to investigate current promising preliminary findings.     

Mitochondrial DNA sequence data reveals association of haplogroup U with psychosis in bipolar disorder

Converging genetic, postmortem gene-expression, cellular, and neuroimaging data implicate mitochondrial dysfunction in bipolar disorder. This study was conducted to investigate whether mitochondrial DNA (mtDNA) haplogroups and single nucleotide variants (SNVs) are associated with sub-phenotypes of bipolar disorder. MtDNA from 224 patients with Bipolar I disorder (BPI) was sequenced, and association of sequence variations with 3 sub-phenotypes (psychosis, rapid cycling, and adolescent illness onset) was evaluated. Gene-level tests were performed to evaluate overall burden of minor alleles for each phenotype. The haplogroup U was associated with a higher risk of psychosis. Secondary analyses of SNVs provided nominal evidence for association of psychosis with variants in the tRNA, ND4 and ND5 genes. The association of psychosis with ND4 (gene that encodes NADH dehydrogenase 4) was further supported by gene-level analysis. Preliminary analysis of mtDNA sequence data suggests a higher risk of psychosis with the U haplogroup and variation in the ND4 gene implicated in electron transport chain energy regulation. Further investigation of the functional consequences of this mtDNA variation is encouraged.     

Association between dopaminergic dysfunction and anxiety in de novo Parkinson's disease

ObjectivesTo explore the relationships between nigrostriatal dysfunction and neuropsychiatric symptoms (including anxiety, depression and apathy) in a large cohort of newly diagnosed, drug-naïve Parkinson disease (PD) patients compared to a cohort of healthy controls (HC).MethodsThis is a cross-sectional analysis of the Parkinson's Progression Markers Initiative (PPMI) cohort at baseline, including 405 PD patients and 187 HC. Nigrostriatal degeneration was evaluated by means of SPECT DAT scan. Relationships between neuropsychiatric symptoms and DAT uptakes were analysed by means of stepwise multiple regression analysis.ResultsIn the PD group, lower DAT uptake in the right caudate was associated with higher STAI trait subscore (β = −2.939, 95%CI: −4.634 to −1.254, p = 0.001). Depression and apathy scores were not related with DAT uptakes. No associations were found in the HC group.ConclusionsOur cross-sectional analysis of the PPMI data shows that lower caudate DAT uptake is associated with higher level of anxiety. The data strengthens the relationship between dopaminergic dysfunction and neuropsychiatric symptoms in early PD.     

Subclinical neurological involvement does not develop if Wilson's disease is treated early

Background & aimsWilson's disease (WD) is a genetic disorder of copper metabolism causing dysfunctions of various organs, mostly the liver and brain. If untreated, WD is fatal, but early treatment results in a good prognosis, although the long-term neurological outcome has not yet been clarified. To address this issue, we evaluated the neurological status of early-treated WD patients without overt nervous system impairment using neurophysiological, neuropsychological and neuroimaging procedures at least 10 years after treatment onset.MethodsThirty-eight WD patients (18 females, aged 24.47 ± 7.50 years), who received an early diagnosis (in presymptomatic or mild/moderate liver disease stages without neurological involvement) and prompt treatment, were clinically evaluated with the Global Assessment Scale. Presentation was hepatic in 36 subjects (95%), while 2 patients (5%) were presymptomatic. A neurophysiological study was performed to explore the central motor conduction time of the upper and lower limbs, and motor cortex excitability using single pulses and paired-pulse transcranial magnetic stimulation. Neuroimages were obtained with brain magnetic resonance scans. Cognitive abilities, and psychiatric and behavioral disturbances were evaluated with neuropsychological tests.ResultsPatients were undergoing treatment with penicillamine (7 patients) or zinc salts (31 patients) with good adherence. They did not present any neurological signs at clinical evaluation or at specific scale of impairment, the mean Global Assessment Scale score was 0.3 ± 0.7. Magnetic resonance imaging, transcranial magnetic stimulation studies and neuropsychological/neuropsychiatric assessment ruled out subclinical involvement.ConclusionsThis study suggests that early diagnosis and treatment of WD may prevent the onset of neurologic damage, even at subclinical level.     

Determinants of denervation-independent depletion of putamen dopamine in Parkinson's disease and multiple system atrophy

BackgroundSevere putamen dopamine depletion characterizes Parkinson's disease (PD) and multiple system atrophy (MSA). The extent of the depletion is greater than can be accounted for by loss of nigrostriatal dopaminergic terminals alone. We used putamen tissue levels and ratios of cysteinyl and parent catechols to explore possible denervation-independent abnormalities of dopamine synthesis and fate in PD and MSA. 5-S-Cysteinyldopa (Cys-DOPA) is produced from spontaneous oxidation of DOPA and 5-S-cysteinyldopamine (Cys-DA) from spontaneous oxidation of DA.MethodsPost-mortem putamen tissue samples from 17 PD and 25 MSA patients and 30 controls were assayed for endogenous catechols including DA, its cytoplasmic metabolites (Cys-DA, 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethanol, and 3,4-dihydroxyphenylacetaldehyde), and tyrosine hydroxylation products proximal to DA (DOPA and Cys-DOPA).ResultsThe PD and MSA groups did not differ in mean values of parent or cysteinyl catechols, and the data for the two groups were lumped. In the patients an index of vesicular storage of DA (the ratio of DA to the sum of its cytoplasmic metabolites) averaged 54% of control (p = 0.001), and an index of L-aromatic-amino-acid decarboxylase (LAAAD) activity (the ratio of DA and the sum of its cytoplasmic metabolites to the sum of DOPA + Cys-DOPA) averaged 21% of control (p < 0.0001). An index of innervation (the sum of DOPA + Cys-DOPA) averaged 63% of control (p = 0.01).InterpretationBased on patterns of parent and cysteinyl catechols in putamen, PD and MSA involve decreased vesicular uptake and decreased LAAAD activity in the residual dopaminergic terminals. The combination seems to contribute importantly to dopamine depletion in these diseases.     

Major depression induces oxidative stress and platelet hyperaggregability

We have previously demonstrated an impairment of intraplatelet l-arginine-nitric oxide-cGMP pathway in major depression (MD) associated to platelet dysfunction. Here, we evaluated arginase pathway and phosphodiesterase 5 (PDE5) expression in platelets, systemic and intraplatelet oxidative status in untreated MD patients, and their effects on platelet aggregation. Blood samples were collected from 22 treatment naive MD patients (31 ± 2 yr) and 27 healthy subjects (33 ± 2 yr). MD patients presented with an activation of platelet arginase II, which competes with l-arginine for the production of nitric oxide (NO). An increase in protein carbonylation, overexpression of NADPH oxidase and PDE5, an enzyme that inactivates cGMP, was observed in platelets from MD patients compared to controls. In this context, platelet hyperaggregability was found in MD patients. On the other hand, antioxidant enzymes catalase, glutathione peroxidase and superoxide dismutase activities in serum and in platelets did not differ between groups. The increased activation of intraplatelet arginase and platelet aggregability, in addition to an overexpression of PDE5 and oxidative stress may contribute to alterations in l-arginine–NO–cGMP pathway and in platelet function, and consequently to the increased thrombotic risk in MD.     

Hearing loss mediates executive function impairment in sleep-disordered breathing

BackgroundSleep-disordered breathing (SDB) is often co-morbid with conductive hearing loss in early childhood due to a shared aetiology of adenotonsillar hypertrophy. Hearing loss is independently associated with impairment of executive function and behavioural difficulties. We hypothesised that these impairments in children with SDB may be mediated through hearing loss.MethodsFifty-eight children including 37 snorers awaiting adenotonsillectomy and 21 healthy non-snoring controls, aged 3–5 years, were assessed with pure tone audiometry, Strengths and Difficulties (SDQ), Behaviour Rating of Executive Function (BRIEF-P), and Childhood Middle Ear Disease and Hearing questionnaires. Polysomnography in snoring children generated an obstructive apnoea/hypopnea index (OAHI). Two regression models examined the effect of SDB and the mediating impact of hearing loss on BRIEF and SDQ.ResultsSnoring children had significantly poorer hearing, greater past exposure to hearing loss, and higher total SDQ and BRIEF-P scores than non-snoring controls. The first regression model, including all children, demonstrated that the impact of snoring on BRIEF_P, but not SDQ, was entirely mediated by a history of hearing loss exposure but not same-day audiometry. The second model examined snoring children only, categorising the group into 12 with obstructive sleep apnoea (OSA) (OAHI ≥ 5) and 25 without OSA. OSA had a direct effect on SDQ scores, but this was not mediated by a history of hearing loss.ConclusionIn early childhood, conductive hearing loss mediates the relationship between SDB, irrespective of severity, and parent report of executive function but not behaviour. Treatment of hearing loss in pre-school SDB might improve executive function.     

Smartphone-based tactile cueing improves motor performance in Parkinson's disease

IntroductionVisual and auditory cueing improve functional performance in Parkinson's disease (PD) patients. However, audiovisual processing shares many cognitive resources used for attention-dependent tasks such as communication, spatial orientation, and balance. Conversely, tactile cues (TC) may be processed faster, with minimal attentional demand, and may be more efficient means for modulating motor-cognitive performance. In this study we aimed to investigate the efficacy and limitations of TC for modulating simple (heel tapping) and more complex (walking) motor tasks (1) over a range of cueing intervals, (2) with/without a secondary motor task (holding tray with cups of water).MethodsTen PD patients (71 ± 9 years) and 10 healthy controls (69 ± 7 years) participated in the study. TCs was delivered through a smart phone attached to subjects' dominant arm and were controlled by a custom-developed Android application.ResultsPD patients and healthy controls were able to use TC to modulate heel tapping (F(3.8,1866.1) = 1008.1, p < 0.001), and partially modulate walking (F(3.5,1448.7) = 187.5, p < 0.001) tasks. In the walking task, PD patients modulated performance over a narrower range of cueing intervals (R² = 0.56) than healthy controls (R² = 0.84; group difference F(3.5,1448.7) = 8.6, p < 0.001). TC diminished synchronization error associated with performance of secondary motor task during walking in PD patients and healthy controls (main effect of Task (F(1,494) = 0.4; p = 0.527), Task X Group interaction (F(1,494) = 0.5; p = 0.493)).ConclusionThis study expands modalities of TC usage for movement modulation and motor-cognitive integration in PD patients. The smartphone TC application was validated as a user-friendly movement modulation aid.     

Neurophysiological studies on atypical parkinsonian syndromes

There have been a relatively large number of experimental investigations using neurophysiological techniques in patients with atypical parkinsonian syndromes (APs), including progressive supranuclear palsy, cortico-basal syndrome and multiple system atrophy. Earlier studies focused on the startle, blink and trigemino-cervical reflexes and showed several brainstem abnormalities. Studies using transcranial magnetic stimulation have revealed a number of abnormalities in primary motor cortex and inter-hemispheric connectivity. More recent studies have highlighted the role of cerebellar dysfunction and have reported altered movement kinematics. Neurophysiological abnormalities in APs reflect degeneration or functional changes at multiple brain levels. In the majority of cases, APs share common abnormalities even though some neurophysiological changes differ among the various APs. Evidence of a correlation between neurophysiological abnormalities and clinical signs and symptoms in APs is limited. This paper provides an update on the results of experimental investigations using neurophysiological techniques in APs and also reviews similarities and differences between APs and Parkinson's disease. The potential role of neurophysiological abnormalities in the clinical context of APs is also discussed.     

Effects of movement imitation training in Parkinson's disease: A virtual reality pilot study

BackgroundHypometria is a clinical motor sign in Parkinson's disease. Its origin likely emerges from basal ganglia dysfunction, leading to an impaired control of inhibitory intracortical motor circuits. Some neurorehabilitation approaches include movement imitation training; besides the effects of motor practice, there might be a benefit due to observation and imitation of un-altered movement patterns. In this sense, virtual reality facilitates the process by customizing motor-patterns to be observed and imitated.ObjectiveTo evaluate the effect of a motor-imitation therapy focused on hypometria in Parkinson's disease using virtual reality.MethodsWe carried out a randomized controlled pilot-study. Sixteen patients were randomly assigned in experimental and control groups. Groups underwent 4-weeks of training based on finger-tapping with the dominant hand, in which imitation was the differential factor (only the experimental group imitated). We evaluated self-paced movement features and cortico-spinal excitability (recruitment curves and silent periods in both hemispheres) before, immediately after, and two weeks after the training period.ResultsMovement amplitude increased significantly after the therapy in the experimental group for the trained and un-trained hands. Motor thresholds and silent periods evaluated with transcranial magnetic stimulation were differently modified by training in the two groups; although the changes in the input–output recruitment were similar.ConclusionsThis pilot study suggests that movement imitation therapy enhances the effect of motor practice in patients with Parkinson's disease; imitation-training might be helpful for reducing hypometria in these patients. These results must be clarified in future larger trials.     

Sensing the body in chronic pain: A review of psychophysical studies implicating altered body representation

There is growing evidence that chronic pain conditions can have an associated central pathology, involving both cortical reorganisation and an incongruence between expected and actual sensory–motor feedback. While such findings are primarily driven by the recent proliferation of neuroimaging studies, the psychophysical tasks that complement those investigations have received little attention. In this review, we discuss the literature that involves the subjective appraisal of body representation in patients with chronic pain. We do so by examining three broad sensory systems that form the foundations of the sense of physical self in patients with common chronic pain disorders: (i) reweighting of proprioceptive information; (ii) altered sensitivity to exteroceptive stimuli; and, (iii) disturbed interoceptive awareness of the state of the body. Such findings present compelling evidence for a multisensory and multimodal approach to therapies for chronic pain disorders.     

NR2B subunit in the prefrontal cortex: A double-edged sword for working memory function and psychiatric disorders

The prefrontal cortex (PFC) is a brain region featured with working memory function. The exact mechanism of how working memory operates within the PFC circuitry is unknown, but persistent neuronal firing recorded from prefrontal neurons during a working memory task is proposed to be the neural correlate of this mnemonic encoding. The PFC appears to be specialized for sustaining persistent firing, with N-methyl-d-aspartate (NMDA) receptors, especially slow-decay NR2B subunits, playing an essential role in the maintenance of sustained activity and normal working memory function. However, the NR2B subunit serves as a double-edged sword for PFC function. Because of its slow kinetics, NR2B endows the PFC with not only “neural psychic” properties, but also susceptibilities for neuroexcitotoxicity and psychiatric disorders. This review aims to clarify the interplay among working memory, the PFC, and NMDA receptors; demonstrate the importance of NR2B in the maintenance of persistent activity; understand the risks and vulnerabilities of how NR2B is related to the development of neuropsychiatric disorders; identify gaps that currently exist in our understanding of these processes; and provide insights regarding future directions that may clarify these issues. We conclude that the PFC is a specialized brain region with distinct delayed maturation, unique neuronal circuitry, and characteristic NMDA receptor function. The unique properties and development of NMDA receptors, especially enrichment of NR2B subunits, endow the PFC with not only the capability to generate sustained activity for working memory, but also serves as a major vulnerability to environmental insults and risk factors for psychiatric disorders.     

Early life exposure to sevoflurane impairs adulthood spatial memory in the rat

Sevoflurane is a general anesthetic commonly used in the pediatric setting because it is sweet-smelling, nonflammable, fast acting and has a very short recovery time. Although recent clinical data suggest that early anesthesia exposure is associated with subsequent learning and memory problems, it is difficult to determine the exact scope of developmental neurotoxicity associated with exposure to specific anesthetics such as sevoflurane. This is largely due to inconsistencies in the literature. Thus, in the present studies we evaluated the effect of early life exposure to sevoflurane (1%, 2%, 3% or 4%) on adulthood memory impairment in Sprague-Dawley rats. Animals were exposed to different regimens of sevoflurane anesthesia on postnatal days (PNDs) 3, 7, or 14 or at 7 weeks (P7W) of age and spatial memory performance was assessed in adulthood using the Morris Water Maze (MWM). Rats exposed to sevoflurane exhibited significant memory impairment which was concentration and exposure duration dependent. Disruption of MWM performance was more severe in animals exposed on both PNDs 3 and 7 than in animals exposed on both PNDs 3 and 14. The younger the animal's age at the time of exposure, the more significant the effect on later MWM performance. Compared to the neonates, animals exposed at P7W were relatively insensitive to sevoflurane: memory was impaired in this group only after repeated exposures to low doses or single exposures to high doses. Early life exposure to sevoflurane can result in spatial memory impairments in adulthood and the shorter the interval between exposures, the greater the deficit.