α-Synuclein Regulates Development and Function of Cholinergic Enteric Neurons in the Mouse Colon.

Alpha-Synuclein (α-Syn) is expressed in the central nervous system and the nervous system of the gut (enteric nervous system, ENS), and is well known to be the major constituent of Lewy bodies which are the hallmark of Parkinson's disease. Gastrointestinal disorders frequently manifest several years before motor deficits develop in Parkinson's patients. Despite extensive research on pathological rodent models, the physiological role of α-Syn in the normal ENS is unclear hampering analysis of its neuropathology. We compared the ENS in colons of α-Syn-knockout (α-Syn KO) and wild-type mice using immunohistochemistry and calcium-imaging of responses to synaptic input. We found that α-Syn is predominantly expressed in cholinergic varicosities, which contain vesicular acetylcholine transporter. α-Syn KO mice had higher enteric neuron density and a larger proportion of cholinergic neurons, notably those containing calretinin, demonstrating a role for α-Syn in regulating development of these neurons. Moreover, α-Syn deletion enhanced the amplitude of synaptically activated [Ca2+]i transients that are primarily mediated by acetylcholine activating nicotinic receptors suggesting that α-Syn modulates the availability of acetylcholine in enteric nerve terminals.

Demographics of healthcare professionals' knowledge and attitude toward deceased organ donation: Survey of critical care areas in a tertiary hospital.

INTRODUCTION: Organ donation rate in Malaysia is amongst the lowest in the World. Healthcare professionals (HCPs) working in critical care areas play an important role in the deceased organ donation (DOD) process. This study seeks to identify the demographics of HCPs working in the critical care areas and their knowledge and attitudes toward the DOD process. METHOD: A cross-sectional survey on the demographics, knowledge and attitudes of the doctors and nurses working in critical care areas was undertaken by the random sampling method, using a validated, structured questionnaire. HCP's knowledge and attitudes towards brain death (BD), DOD, organ transplantation (OT), and possession of organ donor card were compared against their demographics. RESULTS: Four hundred and twelve (72.9%) out of the total 565 HCPs in critical care areas responded of whom 163 (39.6%) were doctors and 249 (60.4%) were nurses. After adjusting for other factors, department of work and profession were highly correlated with the overall knowledge score (p<0.001 and p=0.003 respectively) and knowledge about BD (p<0.001 and p=0.013 respectively). HCPs from the neurosurgical intensive care unit (p<0.001) and doctors (p<0.001) had higher mean knowledge scores compared to their counterparts. Profession was most significantly correlated with having a positive attitude towards BD (p<0.001) and OT (p<0.001). CONCLUSION: Department, profession and ethnicity were the demographic characteristics that correlated with knowledge and attitudes of HCPs on organ donation. Efforts to improve DOD rates in Malaysia should include targeted interventions to address the knowledge and attitudes of HCPs working in critical care areas.

Enteric nervous system assembly: Functional integration within the developing gut.

Co-ordinated gastrointestinal function is the result of integrated communication between the enteric nervous system (ENS) and "effector" cells in the gastrointestinal tract. Unlike smooth muscle cells, interstitial cells, and the vast majority of cell types residing in the mucosa, enteric neurons and glia are not generated within the gut. Instead, they arise from neural crest cells that migrate into and colonise the developing gastrointestinal tract. Although they are "later" arrivals into the developing gut, enteric neural crest-derived cells (ENCCs) respond to many of the same secreted signalling molecules as the "resident" epithelial and mesenchymal cells, and several factors that control the development of smooth muscle cells, interstitial cells and epithelial cells also regulate ENCCs. Much progress has been made towards understanding the migration of ENCCs along the gastrointestinal tract and their differentiation into neurons and glia. However, our understanding of how enteric neurons begin to communicate with each other and extend their neurites out of the developing plexus layers to innervate the various cell types lining the concentric layers of the gastrointestinal tract is only beginning. It is critical for postpartum survival that the gastrointestinal tract and its enteric circuitry are sufficiently mature to cope with the influx of nutrients and their absorption that occurs shortly after birth. Subsequently, colonisation of the gut by immune cells and microbiota during postnatal development has an important impact that determines the ultimate outline of the intrinsic neural networks of the gut. In this review, we describe the integrated development of the ENS and its target cells.

Tract-Based Spatial Statistics in Preterm-Born Neonates Predicts Cognitive and Motor Outcomes at 18 Months.

BACKGROUND AND PURPOSE: Adverse neurodevelopmental outcome is common in children born preterm. Early sensitive predictors of neurodevelopmental outcome such as MR imaging are needed. Tract-based spatial statistics, a diffusion MR imaging analysis method, performed at term-equivalent age (40 weeks) is a promising predictor of neurodevelopmental outcomes in children born very preterm. We sought to determine the association of tract-based spatial statistics findings before term-equivalent age with neurodevelopmental outcome at 18-months corrected age. MATERIALS AND METHODS: Of 180 neonates (born at 24-32-weeks' gestation) enrolled, 153 had DTI acquired early at 32 weeks' postmenstrual age and 105 had DTI acquired later at 39.6 weeks' postmenstrual age. Voxelwise statistics were calculated by performing tract-based spatial statistics on DTI that was aligned to age-appropriate templates. At 18-month corrected age, 166 neonates underwent neurodevelopmental assessment by using the Bayley Scales of Infant Development, 3rd ed, and the Peabody Developmental Motor Scales, 2nd ed. RESULTS: Tract-based spatial statistics analysis applied to early-acquired scans (postmenstrual age of 30-33 weeks) indicated a limited significant positive association between motor skills and axial diffusivity and radial diffusivity values in the corpus callosum, internal and external/extreme capsules, and midbrain (P < .05, corrected). In contrast, for term scans (postmenstrual age of 37-41 weeks), tract-based spatial statistics analysis showed a significant relationship between both motor and cognitive scores with fractional anisotropy in the corpus callosum and corticospinal tracts (P < .05, corrected). Tract-based spatial statistics in a limited subset of neonates (n = 22) scanned at <30 weeks did not significantly predict neurodevelopmental outcomes. CONCLUSIONS: The strength of the association between fractional anisotropy values and neurodevelopmental outcome scores increased from early-to-late-acquired scans in preterm-born neonates, consistent with brain dysmaturation in this population.

Temporal lobe epilepsy and affective disorders: the role of the subgenual anterior cingulate cortex.

OBJECTIVE: Reduced deactivation within the default mode network (DMN) is common in individuals with primary affective disorders relative to healthy volunteers (HVs). It is unknown whether similar network abnormalities are present in temporal lobe epilepsy (TLE) patients with a history of affective psychopathology. METHODS: 17 TLE patients with a lifetime affective diagnosis, 31 TLE patients with no formal psychiatric history and 30 HVs were included. We used a visuo-spatial 'n-back' paradigm to compare working memory (WM) network activation between these groups. Post hoc analyses included voxel-based morphometry and diffusion tensor imaging. The Beck Depression Inventory-Fast Screen and Beck Anxiety Inventory were completed on the day of scanning. FINDINGS: Each group activated the fronto-parietal WM networks and deactivated the typical DMN in response to increasing task demands. Group comparison revealed that TLE patients with lifetime affective morbidity showed significantly greater deactivation in subgenual anterior cingulate cortex (sACC) than either the TLE-only or the HVs (p<0.001). This effect persisted after covarying for current psychotropic medication and severity of current depressive/anxiety symptoms (all p<0.001). Correlational analysis revealed that this finding was not driven by differences in task performance. There were no significant differences in grey matter volume or structural connectivity between the TLE groups. CONCLUSIONS: Our results provide novel evidence suggesting that affective psychopathology in TLE has a neurobiological correlate, and in this context the sACC performs differently compared with network activity in primary affective disorders.

Interictal psychosis following temporal lobe surgery: dentate gyrus pathology.

BACKGROUND: De novo interictal psychosis, albeit uncommon, can develop in patients following temporal lobe surgery for epilepsy. Pathological alterations of the dentate gyrus, including cytoarchitectural changes, immaturity and axonal reorganization that occur in epilepsy, may also underpin co-morbid psychiatric disorders. Our aim was to study candidate pathways that may be associated with the development of interictal psychosis post-operatively in patients with hippocampal sclerosis (HS). METHOD: A total of 11 patients with HS who developed interictal psychosis (HS-P) post-operatively were compared with a matched surgical HS group without psychosis (HS-NP). Resected tissues were investigated for the extent of granule cell dispersion, mossy fibre sprouting and calbindin expression in the granule cells. We quantified doublecortin, mini-chromosome maintenance protein 2 (MCM2) and reelin-expressing neuronal populations in the dentate gyrus as well as the distribution of cannabinoid type 1 receptor (CBR1). RESULTS: The patterns of neuronal loss and gliosis were similar in both groups. HS-P patients demonstrated less mossy fibre sprouting and granule cell dispersion (p < 0.01) and more frequent reduction in calbindin expression in granule cells. There were no group differences in the densities of immature MCM2, doublecortin and reelin-positive cells. CBR1 labelling was significantly lower in Cornu ammonis area CA4 relative to other subfields (p < 0.01); although reduced staining in all hippocampal regions was noted in HS-P compared with HS-NP patients, the differences were not statistically significant. CONCLUSIONS: The alterations in dentate gyrus pathology found in HS-P patients could indicate underlying differences in the cellular response to seizures. These mechanisms may predispose to the development of psychosis in epilepsy and warrant further investigation.

Inpatient treatment of functional motor symptoms: a long-term follow-up study.

Functional neurological disorders are common, disabling and often difficult to treat. There is little consensus on the best approach to management. Multidisciplinary inpatient approaches are employed in some centres for patients with severe refractory symptoms, but their efficacy and, in particular, long-term outcomes are uncertain. We conducted a study using questionnaires completed retrospectively by patients treated at a specialised multidisciplinary inpatient programme at the National Hospital for Neurology and Neurosurgery. Consecutive patients with functional motor symptoms admitted to this centre between 2006 and 2008 were invited to participate. Questionnaires were sent at least 2 years after discharge. We contacted 32 patients, and 26 responded. The majority had symptoms for at least 3 years prior to admission; 58 % of patients reported benefit from the programme on discharge. This self-reported benefit to symptoms and function was after a 2-year follow-up period in the majority of patients, but return to work or cessation of health-related financial benefits was uncommon even in those who improved. Seventy-four percent of those questioned stated they would recommend the programme to others with similar symptoms. Attribution of symptoms to stress or emotional state was correlated with favourable outcome. Our data suggest that multidisciplinary inpatient treatment for patients with refractory functional motor symptoms provides self-reported benefit in the long-term. Prospective analysis of such interventions and the determinants of benefit need assessment in order to improve the service and target treatment to patients most likely to benefit.

Activation of neuronal SST1 and SST2 receptors decreases neurogenic secretion in the guinea-pig jejunum.

BACKGROUND: Vasoactive intestinal peptide (VIP) submucosal neurons, the main regulators of gut secretion, display inhibitory postsynaptic potentials mediated by somatostatin (SOM) acting on SST(1) and SST(2) receptors (SSTR(1), SSTR(2)) in the guinea-pig small intestine. We investigated the implications of this for neurally-evoked mucosal secretion. METHODS: Mucosal-submucosal preparations from guinea-pig jejunum were mounted in Ussing chambers to measure Cl(-) secretion, measured by short circuit current (I(sc)). All drugs were added serosally. Veratridine (1 µmol L(-1)) was used to stimulate neurons and provide a robust secretory response for pharmacological testing.5-hydroxytrptamine (5-HT, 300 nmol L(-1)) was used to specifically activate non-cholinergic secretomotor neurons, while 1,1-dimethyl-4-phenylpiperazinium (DMPP, 10 µmol L(-1)) was used to stimulate all secretomotor neurons. KEY RESULTS: Somatostatin (50 nmol L(-1)) induced a tetrodotoxin (TTX, 1 µmol L(-1))-sensitive decrease in secretion. Somatostatin also reduced the veratridine-induced increase in I(sc). The effects of SOM were significantly reduced by blocking SSTR(1) and SSTR(2) individually or together. Blocking SSTR(1) abolished the inhibition produced by SOM. Quantitative PCR demonstrated that SSTR(1) and SSTR(2) were much more highly expressed in the submucosa than the mucosa. Submucosal SSTR(1) expression was several fold higher than SSTR(2). Responses to DMPP (biphasic) and 5-HT (monophasic) were TTX-sensitive. Somatostatin significantly reduced the 5-HT-induced increase in I(sc), and the second, more sustained phase evoked by DMPP. CONCLUSIONS & INFERENCES: These data suggest that SOM exerts its antisecretory effects by suppressing firing of VIP secretomotor neurons, rather than via a direct action on mucosal enterocytes.

Psychiatric outcome of surgery for temporal lobe epilepsy and presurgical considerations.

In recent years, surgery has become a treatment option for some patients with intractable epilepsy, particularly those with temporal lobe epilepsy. Psychiatric disturbances may complicate the postsurgical outcome in some patients and de novo psychiatric symptoms have been reported. In many but not all epilepsy surgical centres, a psychiatric assessment is included as part of the presurgical evaluation of potential candidates for surgery. This review indicates that affective disorders, namely, depression and anxiety, and psychosis are the most frequently reported postsurgical psychiatric disturbances. Whilst there are no absolute psychiatric contraindications to surgery, certain pre-existing psychiatric conditions may need careful consideration as there may be a risk of postsurgical psychiatric complications. Routine pre- and postsurgical psychiatric evaluations in patients undergoing epilepsy surgery are recommended. Clinicians involved in the care of surgical candidates should be aware of the possible psychiatric complications following surgery and ensure that the psychiatric risks are discussed with the patient and family.

Comparison of microshear bond strengths of four self-etching bonding systems to enamel using two test methods.

BACKGROUND: Recent advances in enamel and dentine adhesive technology have resulted in the emergence of many new adhesive systems. Self-etching bonding systems do not require a separate etching step and the newest systems are the "all-in-one" systems which combine etching, priming and bonding into a single application. This study reports laboratory enamel microshear bond strengths of a self-etching priming and three all-in-one systems and also evaluates two different microshear bond test methods. METHODS: One hundred and nineteen enamel specimens were bonded (0.8 mm diameter) with either Clearfil Protect Bond (Kuraray), Xeno III (Dentsply), G Bond (GC) or One-Up Bond F (Tokuyama) using Palfique Estelite resin composite and stored in 37 degrees Celsius water for seven days. The microshear bond test method used either a blade or wire to apply the shear stress. Results were analysed with one-way ANOVA and post hoc (Tukey) multiple comparison analysis. RESULTS: Clearfil Protect Bond demonstrated higher and more consistent bond strengths than Xeno III, G Bond or One-Up Bond F. The wire method showed much greater reliability in results, with a coefficient of variation half that of the blade method. CONCLUSIONS: All-in-one adhesives seem to be less reliable than the two-step self-etching priming adhesive when bonding to enamel. Test method can significantly affect results in the microshear bond test method.

Investigating regional white matter in schizophrenia using diffusion tensor imaging.

Diffusion tensor imaging (DTI) was used to investigate regional white matter in vivo in patients with schizophrenia. DTI is capable of providing information about the organization of white matter tracts and has only recently been used to study schizophrenia. In this study, a voxel based analysis of DTI maps in 14 patients and 19 controls did not reveal any areas of significant differences in DTI measures in white matter. The findings suggest that the structural integrity of white matter in these patients was not disrupted. These results are discussed in relation to previous studies reporting positive findings. It is concluded that further studies using DTI in larger samples, improved and standardised methods of data acquisition and analysis are needed.

Neuropathological abnormalities in schizophrenia: evidence from magnetization transfer imaging.

Post-mortem and structural brain imaging studies in schizophrenia have reported macroscopic changes such as global and regional cortical volume reductions, but it has been more difficult to characterize the histopathological changes that underlie these abnormalities. Magnetization transfer imaging (MTI), a novel MRI technique, more sensitive to subtle or early neuropathological changes than conventional MRI, provides a quantitative measure of macromolecular structural integrity represented by the magnetization transfer ratio (MTR). In this study, we used MTI to examine 25 patients with schizophrenia compared with 30 age-matched controls. A voxel-based analysis of the MTR maps revealed widespread MTR reductions in the cortex unrelated to volume reduction, predominantly in the frontal and temporal regions, in the schizophrenic patients when compared with controls. MTR reductions in bilateral parieto-occipital cortex and the genu of the corpus callosum were associated with the severity of negative symptoms in the schizophrenic patients. However, MTR changes were not related to other clinical variables of age, duration of illness and current dose of antipsychotic medication. This study demonstrates that MTR abnormalities in the cortex can be detected in chronic schizophrenia that may reflect subtle neuropathological changes involving neurones or neuronal processes. Longitudinal studies are needed to determine whether these abnormalities are related to disease progression or other disease manifestations such as cognitive changes.

A comparison of neuropsychological deficits in primary and secondary progressive multiple sclerosis.

Neuropsychological deficits and the relationship to brain pathology were examined in 13 primary progressive (PP) and 12 secondary progressive (SP) multiple sclerosis patients with a similar duration of the progressive phase and comparable physical disability. A battery of neuropsychological tests to assess attention, short-term and working memory was administered to the patients, and their performance was compared to that of 20 healthy controls matched for age and premorbid IQ. Total cerebral lesion load on T2-weighted magnetic resonance imaging was measured in the patients. Both PP and SP patients performed significantly worse than controls in most of the neuropsychological tests. There were only subtle differences between SP and PP on the working memory task although magnetic resonance imaging lesion load was significantly higher in SP than in PP patients. In this exploratory study only subtle differences in cognitive impairment were detected between SP and PP patients matched for physical disability and relevant illness features. The results also suggest that the severity of cognitive impairment cannot be fully explained by the extent of abnormalities detected on conventional T2-weighted magnetic resonance images, and that other pathological abnormalities such as in normal-appearing white matter are likely to be involved.

Neuropathological abnormalities of the corpus callosum in schizophrenia: a diffusion tensor imaging study.

OBJECTIVES: Diffusion tensor imaging (DTI), a technique capable of examining water diffusion in different tissues and the organisation of white matter tracts, was used to investigate the neuropathology of the corpus callosum in vivo in patients with schizophrenia. METHODS: Diffusion tensor imaging was performed in 20 schizophrenic patients and 25 healthy controls. Two complementary measures, mean diffusivity and fractional anisotropy, which are considered to be sensitive indices of axonal integrity, were obtained from regions of interest in the genu (anterior) and splenium (posterior) of the corpus callosum. RESULTS: Mean diffusivity was significantly increased and fractional anisotropy significantly reduced in the splenium but not the genu of the corpus callosum in the schizophrenic group compared with controls. There were no significant sex differences in the DTI measures for either the schizophrenic or control group. Clinical variables such as age, duration of illness, dose of antipsychotic medication, and schizophrenic symptoms did not predict the DTI changes in the schizophrenic patients. CONCLUSIONS: The presence of DTI changes in the splenium but not the genu of the corpus callosum suggests that there may be a focal disruption of commisural connectivity in schizophrenia. However, these findings do not exclude the possibility of abnormalities in other areas of the corpus callosum or other regions of white matter and further research using different methods of analysis may enable us to clarify this. Diffusion tensor imaging is a valuable tool in investigating the structure of white matter in schizophrenia.

In vivo investigation of white matter pathology in schizophrenia with magnetisation transfer imaging.

OBJECTIVES: This study is the first to use magnetisation transfer imaging (MTI), a technique sensitive to myelin and axonal abnormalities, to investigate the white matter in vivo in patients with schizophrenia. METHODS: MTI was performed in 25 schizophrenic patients and 30 healthy controls. A region of interest (ROI) approach was used to obtain magnetisation transfer ratios (MTRs) in several regions of cerebral white matter. RESULTS: MTR values were significantly reduced in the right and left temporal regions in schizophrenic patients compared with controls (p<0.001). Clinical variables such as age, duration of symptoms, schizophrenic symptomatology, and soft neurological signs did not predict this reduction in MTR. There were no MTR abnormalities in the other regions sampled. However, the correlation between the left and right frontal MTR values was marginally significantly different in schizophrenic patients compared with controls suggesting that subtle differences in interhemispheric connections may be present. CONCLUSIONS: Subtle white matter pathology, most likely related to myelin and axonal abnormalities, can be detected in the temporal lobes in schizophrenic patients. MTI may be a useful tool in investigating the white matter in schizophrenia.

Correlates of executive function in multiple sclerosis: the use of magnetic resonance spectroscopy as an index of focal pathology.

Proton magnetic resonance spectroscopy (MRS) was performed in a group of patients with multiple sclerosis (MS) and matched control subjects to examine the relationship between frontal lobe pathology and performance on tests of executive function. The N-acetyl aspartate/creatine ratio (NAA/Cr) was significantly reduced in frontal lesions and/or normal-appearing white matter in the patient group compared with the control group, but choline/creatine ratios did not differ. Although MRS abnormalities and executive deficits were not correlated for MS patients as a group, a few patients with more severe abnormalities of NAA/Cr ratio performed worse than other patients on the spatial working memory test, suggesting that subtle frontal neuropathological abnormalities detected by MRS may contribute to executive deficits. Further investigation is warranted to determine the value of MRS as an index of the pathophysiological processes leading to cognitive deficit.

Neuropsychological deficits in multiple sclerosis after acute relapse.

OBJECTIVES: To examine cognitive and neurological changes and their relation to brain pathology in patients with multiple sclerosis during acute relapse. METHODS: Thirteen patients with multiple sclerosis were examined with a battery of neuropsychological tests during acute relapse and six weeks later. Their performance was compared with the performance of 10 controls matched for age and premorbid IQ. Gadolinium (Gd) enhanced MRI was also performed in patients on both occasions. RESULTS: The patients with multiple sclerosis performed significantly worse than controls on most tests of attention and memory during acute relapse and in remission. At follow up there was a significant or trend of improvement in performance on some tests of attention for patients in whom the Gd enhanced lesion load had decreased. In this subgroup of patients, their improvement also correlated significantly with the reduction in acute lesion load. CONCLUSIONS: The findings suggest that certain neuropsychological deficits detected during an acute relapse may be reversible, particularly in patients who initially have mild cognitive impairment.

Interrogative suggestibility in patients with conversion disorders.

We tested the hypothesis that increased interrogative suggestibility may contribute to the shaping and maintaining of conversions symptoms. Interrogative suggestibility was measured in 12 patients with conversion disorder and 10 control patients with confirmed neurological disease matched for age, premorbid intelligence, and as closely as possible in terms of their neurological symptoms to the patients with conversion disorder. Our observations do not support the contention that individual differences in interrogative suggestibility are of importance in the etiology of conversion disorders.