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Intracellular copper [Cu(I)] has been hypothesized to play role in the differentiation of the neurons. This necessitates understanding the role of Cu(I) not only in the neurons but also in the glia considering their anatomical proximity, contribution towards ion homeostasis, and neurodegeneration. In this study, we did a systematic investigation of the changes in the cellular copper homeostasis during neuronal and glial differentiation and the pathways triggered by them. Our study demonstrates increased mRNA for the plasma membrane copper transporter CTR1 leading to increased Cu(I) during the neuronal (PC-12) differentiation. ATP7A is retained in the trans-Golgi network (TGN) despite high Cu(I) demonstrating its utilization towards the neuronal differentiation. Intracellular copper triggers pathways essential for neurite generation and ERK1/2 activation during the neuronal differentiation. ERK1/2 activation also accompanies the differentiation of the foetal brain derived neuronal progenitor cells. The study demonstrates that ERK1/2 phosphorylation is essential for the viability of the neurons. In contrast, differentiated C-6 (glia) cells contain low intracellular copper and significant downregulation of the ERK1/2 phosphorylation demonstrating that ERK1/2 activation does not regulate the viability of the glia. But ATP7A shows vesicular localization despite low copper in the glia. In addition to the TGN, ATP7A localizes into RAB11 positive recycling endosomes in the glial neurites. Our study demonstrates the role of copper dependent ERK1/2 phosphorylation in the neuronal viability. Whereas glial differentiation largely involves sequestration of Cu(I) into the endosomes potentially (i) for ready release and (ii) rendering cytosolic copper unavailable for pathways like the ERK1/2 activation.

Significance: Myelin breakdown is likely a key factor in the loss of cognitive and motor function associated with many neurodegenerative diseases. Aim: New methods for imaging myelin structure are needed to characterize and quantify the degradation of myelin in standard whole-brain sections of nonhuman primates and in human brain. Approach: Quantitative birefringence microscopy (qBRM) is a label-free technique for rapid histopathological assessment of myelin structural breakdown following cortical injury in rhesus monkeys. Results: We validate birefringence microscopy for structural imaging of myelin in rhesus monkey brain sections, and we demonstrate the power of qBRM by characterizing the breakdown of myelin following cortical injury, as a model of stroke, in the motor cortex. Conclusions: Birefringence microscopy is a valuable tool for histopathology of myelin and for quantitative assessment of myelin structure. Compared to conventional methods, this label-free technique is sensitive to subtle changes in myelin structure, is fast, and enables more quantitative assessment, without the variability inherent in labeling procedures such as immunohistochemistry.

Significance: Natural brain adaptations often involve changes in synaptic strength. The artificial manipulations can help investigate the role of synaptic strength in a specific brain circuit not only in various physiological phenomena like correlated neuronal firing and oscillations but also in behaviors. High- and low-frequency stimulation at presynaptic sites has been used widely to induce long-term potentiation (LTP) and depression. This approach is effective in many brain areas but not in the basolateral amygdala (BLA) because the robust local GABAergic tone inside BLA restricts synaptic plasticity. Aim: We aimed at identifying the subclass of GABAergic neurons that gate LTP in the BLA afferents from the dorsomedial prefrontal cortex (dmPFC). Approach: Chemogenetic or optogenetic suppression of specific GABAergic neurons in BLA was combined with high-frequency stimulation of the BLA afferents as a method for LTP induction. Results: Chemogenetic suppression of somatostatin-positive interneurons (Sst-INs) enabled the ex vivo LTP by high-frequency stimulation of the afferent but the suppression of parvalbumin-positive interneurons (PV-INs) did not. Moreover, optogenetic suppression of Sst-INs with Arch also enabled LTP of the dmPFC-BLA synapses, both ex vivo and in vivo. Conclusions: These findings reveal that Sst-INs but not PV-INs gate LTP in the dmPFC-BLA pathway and provide a method for artificial synaptic facilitation in BLA.

Author(s): Tan, Chia Jie; Mah, Jaclyn Jia Jun; Goh, Wei Lin; Poon, Eileen; Harunal Rashid, Mohamad Farid; Chan, Alexandre | Abstract: ObjectiveCancer-related cognitive impairment (CRCI) among adolescent and young adult (AYA) cancer patients with noncentral nervous system (CNS) cancers has not been well studied. In this study, we aimed to describe CRCI-associated trends and characteristics among AYA cancer patients.MethodsIn a longitudinal cohort of AYA cancer patients without CNS disease, CRCI was evaluated over 1 year using the Functional Assessment of Cancer Therapy-Cognitive Function Instrument, a self-reported cognitive outcome measure. CRCI prevalence was quantified using the previously established minimal clinically important difference. CRCI-associated longitudinal trends and factors were evaluated with mixed-effects model analysis.ResultsNinety-one patients (mean age = 28.4 ± 6.7 years) were included. Approximately one-third (34.1%) experienced CRCI at least once during the study follow-up. Female gender (P = .02), Indian ethnicity (P l .01), current smokers (P l .01), anxiety/depressive symptoms (P l .01) and fatigue (P l .01) were found to be associated with poorer cognitive function among AYAs.ConclusionsAlthough AYA cancer patients were relatively young and without CNS disease involvement, a significant proportion of them experienced clinically important decline in cognitive function. With improved understanding of this subject, effective strategies can be formulated to promote awareness of CRCI and mitigate its negative effects among AYA cancer patients.

Combination antiretroviral therapy (cART), which is a lifelong therapy for people living with human immunodeficiency virus, has been associated with nephrotoxicity and hepatotoxicity leading to its discontinuation. This study aimed at investigating the ameliorative potential of naringenin and quercetin on cART-induced hepatotoxicity and nephrotoxicity. Seventy male Wistar rats (225–260 g) were divided into seven groups as control, cART, naringenin, quercetin, dimethyl sulfoxide (DMSO), naringenin/cART (CN) and quercetin/cART (CQ). cART (24 mg/kg), naringenin (50 mg/kg) and quercetin (50 mg/kg) were dissolved in 1% v/v DMSO and administered orally for 56 days. Combination of cART and bioflavonoids had significant increase in superoxide dismutase (P

Fiber photometry has been increasingly popular in neuroscience research in freely behaving animals. In combination with genetically encoded calcium indicators, it allows for real-time monitoring of neural activity in neuronal somata, dendrites, and axonal terminals. We developed a multichannel fiber photometry device to map the activity of axonal terminals in a restricted, 100-μm-wide brain region in freely moving mice. This device consists of four bundled multimode fibers, each with a 50-μm core diameter and a scientific complementary metal-oxide semiconductor camera to simultaneously acquire fluorescence. We achieved a sampling rate of 100 frames/s and sufficient sensitivity to acquire data from axonal terminals. To avoid interference with neighboring channels, the recording depth of each channel was restricted to

Calcium imaging is emerging as a popular technique in neuroscience. A major reason is that intracellular calcium transients are reflections of electrical events in neurons. For example, calcium influx in the soma and axonal boutons accompanies spiking activity, whereas elevations in dendrites and dendritic spines are associated with synaptic inputs and local regenerative events. However, calcium transients have complex spatiotemporal dynamics, and since most optical methods visualize only one of the somatic, axonal, and dendritic compartments, a straightforward inference of the underlying electrical event is typically challenging. We highlight experiments that have directly calibrated in vivo calcium signals recorded using fluorescent indicators against electrophysiological events. We address commonly asked questions such as: Can calcium imaging be used to characterize neurons with high firing rates? Can the fluorescent signal report a decrease in spiking activity? What is the evidence that calcium transients in subcellular compartments correspond to distinct presynaptic axonal and postsynaptic dendritic events? By reviewing the empirical evidence and limitations, we suggest that, despite some caveats, calcium imaging is a versatile method to characterize a variety of neuronal events in vivo.

Objective. There is renewed interest in epidural and transcutaneous spinal cord stimulation (SCS) as a therapy following spinal cord injury, both to reanimate paralyzed muscles as well as to potentiate weakened volitional control of movements. However, most work to date has focussed on lumbar SCS for restoration of locomotor function. Therefore, we examined upper-limb muscle responses and modulation of supraspinal-evoked movements by different frequencies of cervical SCS delivered to various epidural and transcutaneous sites in anaesthetized, neurologically intact monkeys. Approach. Epidural SCS was delivered via a novel multielectrode cuff placed around both dorsal and ventral surfaces of the cervical spinal cord, while transcutaneous SCS was delivered using a high carrier frequency through surface electrodes. Main results. Ventral epidural SCS elicited robust movements at lower current intensities than dorsal sites, with evoked motor unit potentials that reliably followed even high-frequency trains. By contrast, the muscle responses to dorsal SCS required higher current intensities and were attenuated throughout the train. However, dorsal epidural SCS and, to a lesser extent, transcutaneous SCS were effective at facilitating supraspinal-evoked responses, especially at intermediate stimulation frequencies. The time- and frequency-dependence of dorsal SCS effects could be explained by a simple model in which transynaptic excitation of motoneurons was gated by prior stimuli through presynaptic mechanisms. Significance. Our results suggest that multicontact electrodes allowing access to both dorsal and ventral epidural sites may be beneficial for combined therapeutic purposes, and that the interaction of direct, synaptic and presynaptic effects should be considered when optimising SCS-assisted rehabilitation.

Neuron cells consist of the soma or cell body, axons, dendritic arbor with multiple branches, and dendritic spines which are the substrates for memory storage and synaptic transmission. Detriments in neuron morphology are suggested to play a key role in cognitive impairments following brain irradiation. Multiple molecular mechanisms are involved in the regulation and stability of neuron morphology, while the effects of radiation on these processes have not been studied extensively. In this report, we consider possible biological targets in neurons for energy deposition (ED) by charged particles that could lead to neuron morphology detriments, and the resulting dose and radiation quality dependence of such detriments. The track structures of heavy ions including high charge and energy (HZE) particles consists of core of high-ED events and a penumbra of sparse ED from δ-ray electrons produced in ionization of target molecules. We consider the role of track structure relative to possible targets causative in the degradation of morphology.

Toll-like receptors (TLRs) are members of the pattern recognition receptor family that detect components of foreign pathogens or endogenous molecules released in response to injury. Recent studies demonstrate that TLRs also have a functional role in regulating neuronal proliferation in the developing brain. This study investigated cellular expression of TLR3 using immunohistochemistry on human brain tissue. The tissue sections analysed contained anterior and lateral periventricular white matter from the frontal and parietal lobes in post-mortem neonatal cases with a postmenstrual age range of 23.6-31.4 weeks. In addition to preterm brains without overt pathology (control), preterm pathology cases with evidence of white matter injuries (WMI) were also examined. In order to identify TLR-positive cells, we utilized standard double-labelling immunofluorescence co-labelling techniques and confocal microscopy to compare co-expression of TLR3 with a neuronal marker (NeuN) or with glial markers (GFAP for astrocytes, Iba-1 for microglia and Olig2 for oligodendrocytes). We observed an increase in the neuronal (28 vs. 17%) and astroglial (38 vs. 21%) populations in the WMI group compared to controls in the anterior regions of the periventricular white matter in the frontal lobe. The increase in neurons and astrocytes in the WMI cases was associated with an increase in TLR3 immunoreactivity. This expression was significantly increased in the astroglia. The morphology of the TLR3 signal in the control cases was globular and restricted to the perinuclear region of the neurons and astrocytes, whilst in the cases of WMI, both neuronal, axonal and astroglial TLR3 expression was more diffuse (i.e., a different intracellular distribution) and could be detected along the extensions of the processes. This study demonstrates for the first time that neurons and glial cells in human neonatal periventricular white matter express TLR3 during development. The patterns of TLR3 expression were altered in the presence of WMI, which might influence normal developmental processes within the immature brain. Identifying changes in TLR3 expression during fetal development may be key to understanding the reduced volumes of grey matter and impaired cortical development seen in preterm infants.

Background The use of filter paper as a simple, inexpensive tool for storage and transportation of blood, ‘Dried Blood Spots’ or Guthrie cards, for diagnostic assays is well-established. In contrast, there are a paucity of diagnostic evaluations of dried cerebrospinal fluid (CSF) spots. These have potential applications in low-resource settings, such as Laos, where laboratory facilities for central nervous system (CNS) diagnostics are only available in Vientiane. In Laos, a major cause of CNS infection is Japanese encephalitis virus (JEV). We aimed to develop a dried CSF spot protocol and to evaluate its diagnostic performance using the World Health Organisation recommended anti-JEV IgM antibody capture enzyme-linked immunosorbent assay (JEV MAC-ELISA). Methodology and Principal Findings Sample volumes, spotting techniques and filter paper type were evaluated using a CSF-substitute of anti-JEV IgM positive serum diluted in Phosphate Buffer Solution (PBS) to end-limits of detection by JEV MAC-ELISA. A conventional protocol, involving eluting one paper punch in 200μl PBS, did not detect the end-dilution, nor did multiple punches utilising diverse spotting techniques. However, pre-cut filter paper enabled saturation with five times the volume of CSF-substitute, sufficiently improving sensitivity to detect the end-dilution. The diagnostic accuracy of this optimised protocol was compared with routine, neat CSF in a pilot, retrospective study of JEV MAC-ELISA on consecutive CSF samples, collected 2009–15, from three Lao hospitals. In comparison to neat CSF, 132 CSF samples stored as dried CSF spots for one month at 25–30°C showed 81.6% (65.7–92.3 95%CI) positive agreement, 96.8% (91.0–99.3 95%CI) negative agreement, with a kappa coefficient of 0.81 (0.70–0.92 95%CI). Conclusions/Significance The novel design of pre-cut filter paper saturated with CSF could provide a useful tool for JEV diagnostics in settings with limited laboratory access. It has the potential to improve national JEV surveillance and inform vaccination policies. The saturation of filter paper has potential use in the wider context of pathogen detection, including dried spots for detecting other analytes in CSF, and other body fluids., Author Summary Japanese encephalitis virus infection is widespread in Asia, and primarily affects children in poor, rural areas. The virus spreads to the brain and spinal cord resulting in significant death and disability. Diagnosis requires testing for the immune response ‘antibody’ specific to Japanese encephalitis virus in the cerebrospinal fluid that surrounds the brain and spinal cord. However, in most areas where the infection occurs there are no laboratory facilities. In the absence of laboratory diagnosis, we have poor knowledge of the extent of the problem in these areas. Dried blood spots on filter paper have been used widely for many years as simple, cost-effective tools for transporting samples for testing. However, there have been few attempts at using dried cerebrospinal fluid spots. We developed a technique for using dried spots to store and test cerebrospinal fluid for antibodies to Japanese encephalitis virus. We compared the results of dried spots with routine neat cerebrospinal fluid in 132 patient samples, and demonstrated excellent agreement between the two tests. This novel method for saturating dried cerebrospinal fluid spots has the potential to enhance our knowledge of Japanese encephalitis virus epidemiology, and inform health policies where they are most needed. It could also be transferred for use in diagnosing other infectious diseases, including using other body fluid samples.

Background/Aims: Accumulating evidence from a relatively small number of prospective studies indicates that exposure to prenatal stress profoundly influences the developing human fetus with consequences that persist into childhood and very likely forever. Methods: Maternal/fetal dyads are assessed at ∼20, ∼25, ∼31 and ∼36 weeks of gestation. Infant assessments begin 24 h after delivery with the collection of cortisol and behavioral responses to the painful stress of the heel-stick procedure and measures of neonatal neuromuscular maturity. Infant cognitive, neuromotor development, stress and emotional regulation are evaluated at 3, 6 12 and 24 months of age. Maternal psychosocial stress and demographic information is collected in parallel with infant assessments. Child neurodevelopment is assessed with cognitive tests, measures of adjustment and brain imaging between 5 and 8 years of age. Results:Psychobiological markers of stress during pregnancy, especially early in gestation, result in delayed fetal maturation, disrupted emotional regulation and impaired cognitive performance during infancy and decreased brain volume in areas associated with learning and memory in 6- to 8-year-old children. We review findings from our projects that maternal endocrine alterations that accompany pregnancy and influence fetal/infant/child development are associated with decreased affective responses to stress, altered memory function and increased risk for postpartum depression. Conclusions: Our findings indicate that the mother and her fetus both are influenced by exposure to psychosocial and biological stress. The findings that fetal and maternal programming occur in parallel may have important implications for long-term child development and mother/child interactions.

An automated dual-resolution serial optical coherence tomography (2R-SOCT) scanner is developed. The serial histology system combines a low-resolution (25 μm / voxel) 3 × OCT with a high-resolution (1.5 μm / voxel) 40 × OCT to acquire whole mouse brains at low resolution and to target specific regions of interest (ROIs) at high resolution. The 40 × ROIs positions are selected either manually by the microscope operator or using an automated ROI positioning selection algorithm. Additionally, a multimodal and multiresolution registration pipeline is developed in order to align the 2R-SOCT data onto diffusion MRI (dMRI) data acquired in the same ex vivo mouse brains prior to automated histology. Using this imaging system, 3 whole mouse brains are imaged, and 250 high-resolution 40 × three-dimensional ROIs are acquired. The capability of this system to perform multimodal imaging studies is demonstrated by labeling the ROIs using a mouse brain atlas and by categorizing the ROIs based on their associated dMRI measures. This reveals a good correspondence of the tissue microstructure imaged by the high-resolution OCT with various dMRI measures such as fractional anisotropy, number of fiber orientations, apparent fiber density, orientation dispersion, and intracellular volume fraction.

The wide scale application of dried blood spots (DBS) as a collection tool for low-cost HIV drug resistance testing requires a greater understanding of the accuracy of DBS for genotype analysis and the stability of DBS under various environmental conditions. Analysis of a 50microl DBS via a single amplicon, nested PCR-based in-house assay (the Burnet genotyping assay) showed an average nucleotide concordance of 98.9% with plasma samples, although only 65% of nucleotide mixtures detected in plasma were also detected within DBS. The analysis of three DBS resulted in the detection of a greater number of nucleotide mixtures (72 and 109 mixtures detected within one and three DBS, respectively, n=10). Two DBS extraction protocols (silica particle; NucliSENS, bioMerieux and spin column extraction; High Pure, Roche) were assessed and found to be equivalent (79% and 84% recovery success respectively, n=19). FTA Elute paper (Whatman) was an inferior DBS collection medium compared to Whatman 903 paper. DBS appeared relatively tolerant to multiple freeze/thaw cycles, with 79% of DBS subjected to ten freeze/thaw cycles successfully amplified compared to 93% of DBS defrosted once (n=14). High temperature (37 degrees C) and high humidity (>90%) substantially impaired DBS recovery within two weeks of storage (38%, n=8), whilst storage at -20 degrees C or 4 degrees C adequately preserved DBS for this period (100% recovery, n=8). Therefore, whilst DBS are suitable for HIV drug resistance surveillance, the use of multiple DBS may be required to ensure accurate detection of minor HIV quasispecies and short-term storage of samples at either 4 degrees C or -20 degrees C is recommended.

Molluscan preparations have yielded seminal discoveries in neuroscience, but the experimental advantages of this group have not, until now, been complemented by adequate molecular or genomic information for comparisons to genetically defined model organisms in other phyla. The recent sequencing of the transcriptome and genome of Aplysia californica, however, will enable extensive comparative studies at the molecular level. Among other benefits, this will bring the power of individually identifiable and manipulable neurons to bear upon questions of cellular function for evolutionarily conserved genes associated with clinically important neural dysfunction. Because of the slower rate of gene evolution in this molluscan lineage, more homologs of genes associated with human disease are present in Aplysia than in leading model organisms from Arthropoda (Drosophila) or Nematoda (Caenorhabditis elegans). Research has hardly begun in molluscs on the cellular functions of gene products that in humans are associated with neurological diseases. On the other hand, much is known about molecular and cellular mechanisms of long-term neuronal plasticity. Persistent nociceptive sensitization of nociceptors in Aplysia displays many functional similarities to alterations in mammalian nociceptors associated with the clinical problem of chronic pain. Moreover, in Aplysia and mammals the same cell signaling pathways trigger persistent enhancement of excitability and synaptic transmission following noxious stimulation, and these highly conserved pathways are also used to induce memory traces in neural circuits of diverse species. This functional and molecular overlap in distantly related lineages and neuronal types supports the proposal that fundamental plasticity mechanisms important for memory, chronic pain, and other lasting alterations evolved from adaptive responses to peripheral injury in the earliest neurons. Molluscan preparations should become increasingly useful for comparative studies across phyla that can provide insight into cellular functions of clinically important genes.

Background: Measurement of the duration of post-traumatic amnesia (PTA) is common practice, serving as an important index of the severity of traumatic brain injury (TBI) and a predictor of functional outcome. However, controversy exists regarding the nature of PTA; some studies indicate that it is a confusional state with symptoms that extend beyond disorientation and amnesia. Objective: To evaluate the contribution of the severity of acute confusion 1 month after TBI to prediction of employment at 1 year after injury, comparing it with PTA duration. Methods: Prospective study involving 171 participants with complete data, who met the study criteria, from 228 consecutive TBI Model System admissions. Outcome measures included weekly administration of the Delirium Rating Scale-Revised-98 (DelRS-R98) to measure the severity of acute confusion. Evaluations closest to 1 month after injury were used for study purposes. Duration of PTA was defined as the interval from injury until two consecutive Galveston Orientation and Amnesia Test scores of ⩾76 were obtained within a period of 24–72 h. Univariable and multivariable logistic regression were used to predict employment status at 1 year after injury. Results: Age, education and DelRS-R98 were significant predictors accounting for 34% of outcome variance. Individuals with greater confusion severity at 1 month after injury, older age and lower levels of education were less likely to be employed at 1 year after injury. Severity of confusion was more strongly associated with employment outcome (r s = −0.39) than was PTA duration (r s = −0.34). Conclusions: In addition to demographic indices, severity of acute confusion makes a unique contribution to predicting late outcome after TBI.

Background: DBS samples collected from a fingerprick typically vary in volume and homogeneity and hence make an accurate quantitative analysis of DBS samples difficult. Results: We report a prototype which first defines a precise liquid volume and subsequently stores it to a conventional DBS matrix. Liquid volumes of 2.2 µl ± 7.1% (n = 21) for deionized water and 6.1 µl ± 8.8% (n = 15) for whole blood have been successfully metered and stored in DBS paper. Conclusion: The new method of collecting a defined volume of blood by DBS sampling has the potential to reduce assay bias for the quantitative evaluation of DBS samples while maintaining the simplicity of conventional DBS sampling.

Background: About 40% of patients with limbic encephalitis do not have detectable CNS antibodies. Some of these patients have immune-mediated limbic encephalitis, but their frequency is unknown. Aims: (1) To determine the spectrum of limbic encephalitis identified on clinical grounds in a single institution, and compare it with that in patients referred for antibody analysis. (2) To correlate clinical outcomes with the cellular location of the autoantigens. Methods: Prospective clinical case studies. Immunohistochemistry with rat brain, live hippocampal neurones, HeLa cells expressing Kv potassium channels and immunoblot. Results: In 4 years, 17 patients were identified in the Hospital of the University of Pennsylvania, Philadelphia, USA, and the serum or CSF samples of 22 patients diagnosed elsewhere were also studied. 9 of our 17 (53%) patients had antibodies to known neuronal antigens (paraneoplastic or voltage gated potassium channels (VGKCs)) and 5 (29%) to novel cell-membrane antigens (nCMAg) typically expressed in the hippocampus and sometimes in the cerebellum. Considering the entire series, 19 of 39 (49%) patients had antibodies to known antigens, and 17 (44%) to nCMAg. Follow-up (2–48 months, median 19 months) was available for 35 patients. When compared with patients with antibodies to intraneuronal antigens, a significant association with response to treatment was found in those with antibodies to cell-membrane antigens in general (VGKC or nCMAg, p = 0.003) or to nCMAg (p = 0.006). Conclusions: (1) 82% of patients with limbic encephalitis prospectively identified on clinical grounds had CNS antibodies; (2) responsiveness to treatment is not limited to patients with VGKC antibodies; (3) in many patients (29% from a single institution), the autoantigens were unknown but were found to be highly enriched in neuronal cell membranes of the hippocampus; and (4) these antibodies are associated with a favourable outcome.

Objective: To characterise magnetoencephalographic spike sources in paediatric patients with auditory auras and recurrent localisation-related epilepsy. Methods: Six patients (four boys and two girls (ages 7–14 years) were retrospectively studied. All patients had auditory auras as part of their initial seizure manifestation, including four patients who underwent previous brain surgery. Scalp video electroencephalography and magnetoencephalography (MEG) were carried out in six patients, intraoperative electrocorticography in three patients and extraoperative intracranial video electroencephalography in one patient. MEG auditory-evoked fields (AEFs) were studied in four patients. Results: Three patients had elementary auditory auras, one had complex auditory aura and two had both complex and elementary auras. All six patients had clustered MEG spike sources with coexisting scattered spike sources. MEG clusters were localised in the superior temporal gyrus with surrounding scatters in four patients (two left and two right); two patients had scattered spikes in the superior temporal gyrus in addition to clustered MEG spike sources in the left inferior and middle frontal gyri or parieto-occipital region. AEFs were located within an MEG cluster in one patient and within 3 cm of a cluster in two patients. Surgical resection, including the regions of MEG clusters, was carried out in four patients. Three of four patients who had previous surgeries were seizure free at 2 years after excision of the MEG cluster region. Conclusions: MEG spike sources clustered in the superior temporal gyrus in six patients with auditory auras. These spike sources were in close proximity or seemed to engulf the magnetic AEF. Areas with MEG spike sources contained the residual or recurrent epileptogenic zone after incomplete cortical excision for lesional epilepsy.

Background: Attentional dysfunction is believed to be a prominent and distinguishing neuropsychological feature of dementia with Lewy bodies (DLB); yet, the specific nature of the attentional deficit and factors that can potentially influence attentional processing in DLB have not been fully defined. Aims: To clarify the nature of the attentional deficit in early-stage DLB relative to patients with early-stage dementia of the Alzheimer’s type (DAT) and elderly controls, and examine the effect of task complexity and type of cognitive load on attentional processing in DLB. Methods: Attentional impairment and fluctuating attention were investigated in three groups of subjects—patients with clinical features of early probable DLB (n = 20), a group with early probable DAT (n = 19) and healthy elderly controls (n = 20)—using an experimental computerised reaction time paradigm. Results: Patients with DLB showed greater attentional impairment and fluctuations in attention relative to patients with DAT and elderly controls. The attentional deficit was generalised in nature but increased in magnitude as greater demands were placed on attentional selectivity. Attentional deficits in DLB were most pronounced under task conditions that required more active recruitment of executive control and visuospatial cognitive processes. Conclusions: Attentional deficits in DLB are widespread and encompass all aspects of attentional function. Deficits in higher cortical function influence the degree of attentional impairment and fluctuating attention, suggesting that attentional processing in DLB is mediated by interacting cortical and subcortical mechanisms. These findings serve to clarify the nature of the attentional deficit in DLB and have potentially important ramifications for our understanding of the neurocognitive underpinnings of fluctuations.

On the basis of preliminary evidence from patients with subarachnoid haemorrhage (SAH), axonal degeneration is thought to be an underestimated pathological feature.A longitudinal study in 17 patients with aneurysmal SAH. Ventricular CSF was collected daily for up to 14 days. The neurofilament heavy chain(SMI35) (NfH(SMI35), a biomarker for axonal damage) was quantified using a standard ELISA (upper limit of normal 0.73 ng/ml). The primary outcome measure was the Glasgow Outcome Score (GOS) at 3 months.Of 148 samples from patients with SAH, pathologically high NfH levels in the CSF were found in 78 (52.7%) samples, compared with 20 (5%) of 416 samples from the reference population (p0.0001). A pathological increase in NfH was observed in all patients with a bad outcome (GOS 1-3) compared with 8% of those with a good outcome (GOS 4-5, p0.0001). This increase typically became significant 7 days after the haemorrhage (p0.01). The result was confirmed by analysing the individual mean NfH concentrations in the CSF (3.45 v 0.37 ng/ml, p0.01), and was reinforced by the inverse correlation of NfH in the CSF with the GOS (r = -0.65, p0.01). Severity of injury was found to be correlated to NfH(SMI35) levels in the CSF (World Federation of Neurological Surgeons, r = 0.63, p0.01 and Glasgow Coma Score, r = -0.61, p0.01).Patients with SAH thus have secondary axonal degeneration, which may adversely affect their outcome.

Background: External anal sphincter (EAS) electromyography (EMG) abnormalities can distinguish multiple system atrophy (MSA) from Parkinson's disease in the first five years after disease onset. However, the prevalence of the abnormalities in the early stages of MSA is unknown. Objectives: To present EAS-EMG data in the various stages of MSA. Methods: 84 patients with "probable" MSA were recruited (42 men, 42 women; mean age 62 years (range 47 to 78); mean disease duration 3.2 years (0.5 to 8.0

To measure interictal circadian rhythm of heart rate (HR) variability in patients with temporal lobe epilepsy (TLE) using a 24 hour ECG recording.Various conventional and dynamic fractal measures of HR variability were analysed in 17 patients with refractory TLE, 20 patients with well controlled TLE, and 37 healthy age and sex matched control subjects.The SD of all RR intervals (p0.01), the measured power spectral components of HR variability (low frequency power (p0.01), high frequency power (p0.05)), and the SD1 (p0.05) and SD2 (p0.01) Poincaré two dimensional vector analysis measurements were suppressed in the patients. This suppression was observed during both day and night time; however, it was more pronounced at night, and nocturnal increase in HR variability usually seen in the normal population could not be detected in the patients. The HR variability measures did not correlate with the duration of epilepsy, the age of the patients, or with the anti-epileptic drugs used.TLE was associated with reduced HR variability, which was more pronounced during night than day, and the nocturnal increase in HR variability was abolished in patients with TLE. The alteration in autonomic regulation of HR variability was similar in patients with both refractory and well controlled TLE.

Background: Recurrent brief isolated episodes of amnesia associated with epileptiform discharges on EEG recordings have been interpreted as a distinct entity termed transient epileptic amnesia (TEA). Patients with TEA often complain of autobiographical amnesia for recent and remote events, but show normal anterograde memory. Objective: To investigate ( a ) accelerated long term forgetting and ( b ) autobiographical memory in a group of patients with TEA. Methods: Seven patients with TEA and seven age matched controls were evaluated on a range of anterograde memory tasks in two sessions separated by 6 weeks and by the Galton-Crovitz test of cued autobiographical memory. Results: Patients with TEA showed abnormal long term forgetting of verbal material, with virtually no recall after 6 weeks. In addition, there was impaired recall of autobiographical memories from the time periods 1985–89 and 1990–94 but not from 1995–1999. Conclusions: TEA is associated with accelerated loss of new information and impaired remote autobiographical memory. There are a number of possible explanations including ongoing subclinical ictal activity, medial temporal lobe damage as a result of seizure, or subtle ischaemic pathology. Future analyses should seek to clarify the relationship between aetiology, seizure frequency, and degree of memory impairment.

Objectives: Glutamate mediated excitotoxicity of the hyperactive subthalamic nucleus (STN) has been reported to contribute to nigral degeneration in Parkinson's disease (PD). Deep brain stimulation of the STN (STN DBS), in its role as a highly effective treatment of severe PD motor complications, has been. thought to inhibit STN hyperactivity and therefore decrease progression of PD.Methods: In a prospective two centre study, disease progression was determined by means of serial F-18-fluorodopa (F-dopa) positron emission tomography (PET) in 30 patients with successful STN DBS over the first 16 (SD 6) months after surgery.Results: Depending on the method of PET data analysis used in the two centres, annual progression rates relative to baseline were 9.5-12.4% in the caudate and 10.7-12.9% in the putamen.Conclusions: This functional imaging study is the first to demonstrate a continuous decline of dopaminergic function in patients with advanced PD under clinically effective bilateral STN stimulation. The rates of progression in patients with STN DBS were within the range of previously reported data from longitudinal imaging studies in PD. Therefore this study could not confirm the neuroprotective properties of DBS in the STN target.

Objectives: The validity of 3 Tesla motor functional magnetic resonance imaging (fMRI) in patients with gliomas involving the primary motor cortex was investigated by intraoperative navigated motor cortex stimulation (MCS). Methods: Twenty two patients (10 males, 12 females, mean age 39 years, range 10–65 years) underwent preoperative fMRI studies, performing motor tasks including hand, foot, and mouth movements. A recently developed high field clinical fMRI technique was used to generate pre-surgical maps of functional high risk areas defining a motor focus. Motor foci were tested for validity by intraoperative motor cortex stimulation (MCS) employing image fusion and neuronavigation. Clinical outcome was assessed using the Modified Rankin Scale. Results: FMRI motor foci were successfully detected in all patients preoperatively. In 17 of 22 patients (77.3%), a successful stimulation of the primary motor cortex was possible. All 17 correlated patients showed 100% agreement on MCS and fMRI motor focus within 10 mm. Technical problems during stimulation occurred in three patients (13.6%), no motor response was elicited in two (9.1%), and MCS induced seizures occurred in three (13.6%). Combined fMRI and MCS mapping results allowed large resections in 20 patients (91%) (gross total in nine (41%), subtotal in 11 (50%)) and biopsy in two patients (9%). Pathology revealed seven low grade and 15 high grade gliomas. Mild to moderate transient neurological deterioration occurred in six patients, and a severe hemiparesis in one. All patients recovered within 3 months (31.8% transient, 0% permanent morbidity). Conclusions: The validation of clinically optimised high magnetic field motor fMRI confirms high reliability as a preoperative and intraoperative adjunct in glioma patients selected for surgery within or adjacent to the motor cortex.

Background: The role of the striatum in language remains poorly understood. Intraoperative electrical stimulation during surgery for tumours involving the caudate nucleus or putamen in the dominant hemisphere might be illuminating. Objectives: To study the role of these structures in language, with the aim of avoiding postoperative definitive aphasia. Methods: 11 patients with cortico-subcortical low grade gliomas were operated on while awake, and striatal functional mapping was done. Intraoperative direct electrical stimulation was used while the patients carried out motor and naming tasks during the resection. Results: In five cases of glioma involving the dominant putamen, stimulations induced anarthria, while in six cases of glioma involving the dominant caudate, stimulations elicited perseveration. There was no motor effect. The striatum was systematically preserved. Postoperatively, all patients except one had transient dysphasia which resolved within three months. Conclusions: There appear to be two separate basal ganglia systems in language, one mediated by the putamen which might have a motor role, and one by the caudate which might have a role in cognitive control. These findings could have implications for surgical strategy in lesions involving the dominant striatum.

Objective: To evaluate interictal language functions in patients with medically intractable left and right sided mesial temporal lobe epilepsy (TLE). Methods: Spontaneous speech, language comprehension, confrontation naming, repetition, reading, writing, and word fluency were examined in 12 patients with left sided TLE and 11 patients with right sided TLE. Results: Four patients out of 23 displayed language deficits in more than one language domain. Three further patients exhibited isolated language deficits. Linguistic deficits were observed in both left TLE and right TLE. In quantitative analyses left and right TLE only differed in spontaneous speech (p = 0.02); no difference was found in other language functions, laterality quotient of Wada test, or overall IQ. Qualitative error analysis of object naming, however, showed typical errors associated only with left TLE. Patients with linguistic deficits were older at testing compared to patients without linguistic deficits (p = 0.003), whereas other factors including side of TLE, handedness, educational level, age at epilepsy onset, and duration of epilepsy did not differ between groups. Conclusions: Possible explanations for these findings include neuronal cell loss and deafferentiation in cortical areas, and disruption of the basal temporal language area pathways. Our study suggests that some patients with chronic mesial TLE exhibit linguistic deficits when specifically tested, and underlines the need to routinely investigate linguistic functions in TLE.

Objective: To assess risk factors and prognosis in patients with refractory status epilepticus (RSE). Methods: We retrospectively analysed all episodes of status epilepticus (SE) treated between 1993 and 2002 on the neurological intensive care unit (NICU) of the Charite-Universitatsmedizin Berlin. The predictive and prognostic features of RSE were compared with non-RSE (NRSE). All patients with "de novo" SE were followed up to identify the possible development of post-SE symptomatic epilepsy. Results: A total of 83 episodes fulfilled our criteria of SE. Of these 43% were refractory to first line anticonvulsants. The mean age of patients with SE was 53.3 (SD 19) years, with only two patients younger than 18 years. Encephalitis was significantly more often the primary cause in RSE (p

Objective: To investigate abnormal prion protein (PrP) deposition in the peripheral nervous system (PNS) in human prion diseases. Methods: Eight patients with prion diseases were examined: three with sporadic Creutzfeldt–Jakob disease (sCJD), two with dural graft associated CJD (dCJD), one with Gerstmann–Straussler–Scheinker disease (GSS) with a PrP P102L mutation (GSS102), and two with a P105L mutation (GSS105). An atypical case of sCJD with PrP plaques in the brain presented clinically with peripheral neuropathy, and showed demyelination in 12% of the teased fibres of the sural nerve. The PNS was investigated by immunohistochemical and western blotting analyses of PrP. Results: In immunohistochemical studies, granular PrP deposits were detected in some neurones of dorsal root ganglia and a few fibres of peripheral nerves and spinal posterior roots in one sCJD and two dCJD patients, but not in GSS102 or GSS105 patients. The atypical case of sCJD with peripheral neuropathy showed no obvious PrP deposition in the nerves. Western blotting analysis of the PNS from the dCJD patients revealed a small amount of protease K resistant PrP in the dorsal root ganglia and peripheral nerves. Conclusions: Abnormal PrP deposition occurs in the dorsal root ganglia and peripheral nerves in sCJD and dCJD. The PrP deposits in the PNS are not correlated with clinical manifestation of peripheral neuropathy in CJD.

Background: Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is favoured over bilateral globus pallidus internus (Gpi) DBS for symptomatic treatment of advanced Parkinson's disease (PD) due to the possibility of reducing medication, despite lack of definitive comparative evidence. Objective: To analyse outcomes after one year of bilateral Gpi or STN DBS, with consideration of influence of selection bias on the pattern of postsurgical medication change. Methods: The first patients to undergo bilateral Gpi (n = 10) or STN (n = 10) DBS at our centre were studied. They were assessed presurgically and one year after surgery (CAPIT protocol). Results: Before surgery the Gpi DBS group had more dyskinesias and received lower doses of medication. At one year, mean reduction in UPDRS off medication score was 35% and 39% in the Gpi and STN groups, respectively (non-significant difference). Dyskinesias reduced in proportion to presurgical severity. The levodopa equivalent dose was significantly reduced only in the STN group (24%). This study high-lights the absence of significant differences between the groups in clinical scales and medication dose at one year. In the multivariate analysis of predictive factors for off-state motor improvement, the presurgical levodopa equivalent dose showed a direct relation in the STN and an inverse relation in the Gpi group. Conclusion: Differences in the patterns of medication change after Gpi and STN DBS may be partly due to a patient selection bias. Both procedures may be equally useful for different subgroups of patients with advanced PD, Gpi DBS especially for patients with lower threshold for dyskinesia.

Objective: To evaluate the long term (4 years) efficacy of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in advanced Parkinson's disease. Methods: We performed a double blind crossover evaluation of the efficacy of DBS of the STN in the "off" medication condition in 10 patients with Parkinson's disease. Assessments included the Unified Parkinson's Disease Rating Scale (UPDRS) part III (motor) and two timed tests (arm tapping and walking). Open evaluation of the effect of stimulation in the off and on drug states preoperatively and at 1 and 4 years postoperatively was also conducted. The latter assessment included the UPDRS parts II (activities of daily living) and III (dyskinesia scale and global assessment) as judged by the patient and examiner. The mean amount of levodopa daily dose at base line, 1 year, and 4 years after surgery was compared. Results: A significant (p

Objective: Drug resistant neurogenic pain can be relieved by repetitive transcranial magnetic stimulation (rTMS) of the motor cortex. This study was designed to assess the influence of pain origin, pain site, and sensory loss on rTMS efficacy. Patients and methods: Sixty right handed patients were included, suffering from intractable pain secondary to one of the following types of lesion: thalamic stroke, brainstem stroke, spinal cord lesion, brachial plexus lesion, or trigeminal nerve lesion. The pain predominated unilaterally in the face, the upper limb, or the lower limb. The thermal sensory thresholds were measured within the painful zone and were found to be highly or moderately elevated. Finally, the pain level was scored on a visual analogue scale before and after a 20 minute session of "real" or "sham" 10 Hz rTMS over the side of the motor cortex corresponding to the hand on the painful side, even if the pain was not experienced in the hand itself. Results and discussion: The percentage pain reduction was significantly greater following real than sham rTMS (-22.9% v -7.8%, p = 0.0002), confirming that motor cortex rTMS was able to induce antalgic effects. These effects were significantly influenced by the origin and the site of pain. For pain origin, results were worse in patients with brainstem stroke, whatever the site of pain. This was consistent with a descending modulation within the brainstem, triggered by the motor corticothalamic output. For pain site, better results were obtained for facial pain, although stimulation was targeted on the hand cortical area. Thus, in contrast to implanted stimulation, the target for rTMS procedure in pain control may not be the area corresponding to the painful zone but an adjacent one. Across representation plasticity of cortical areas resulting from deafferentation could explain this discrepancy. Finally, the degree of sensory loss did not interfere with pain origin or pain site regarding rTMS effects. Conclusion: Motor cortex rTMS was found to result in a significant but transient relief of chronic pain, influenced by pain origin and pain site. These parameters should be taken into account in any further study of rTMS application in chronic pain control.

Objective: Bilateral chronic high frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) has emerged as an appropriate therapy for patients with advanced Parkinson’s disease refractory to medical therapy. Advances in neuroimaging and neurophysiology have led to the development of varied targeting methods for the delivery of this treatment. Intraoperative neurophysiological and clinical monitoring is regarded by many to be mandatory for accurate STN localisation. We have examined efficacy of bilateral STN stimulation using a predominantly magnetic resonance imaging (MRI)-directed technique. Methods: DBS leads were stereotactically implanted into the STN using an MRI directed method, with intraoperative macrostimulation used purely for adjustment. The effects of DBS were evaluated in 16 patients followed up to 12 months, and compared with baseline assessments. Assessments were performed in both off and on medication states, and were based on the Unified Parkinson’s Disease Rating Scale (UPDRS) and timed motor tests. Functional status outcomes were examined using the PDQ-39 quality of life questionnaire. A battery of psychometric tests was used to assess cognition. Results: After 12 months, stimulation in the off medication state resulted in significant improvements in Activities of Daily Living and Motor scores (UPDRS parts II and III) by 62% and 61% respectively. Timed motor tests were significantly improved in the off medication state. Motor scores (UPDRS part III) were significantly improved by 40% in the on medication state. Dyskinesias and off duration were significantly reduced and the mean dose of l-dopa equivalents was reduced by half. Psychometric test scores were mostly unchanged or improved. Adverse events were few. Conclusions: An MRI directed targeting method for implantation of DBS leads into the STN can be used safely and effectively, and results are comparable with studies using intraoperative microelectrode neurophysiological targeting. In addition, our method was associated with an efficient use of operating time, and without the necessary costs of microelectrode recording.

Background: “Normal” pressure hydrocephalus (NPH) is associated with injury to neurotransmitter and neuropeptide systems that recovers after surgery. This could be linked to changes in galanin, a neuropeptide with inhibitory effects on basal forebrain cognitive function. Objective: To examine changes in CSF galanin concentrations in patients with normal pressure hydrocephalus undergoing shunt surgery, and to investigate the relation between these changes and cognitive functioning. Methods: Eight patients underwent surgery for idiopathic normal pressure hydrocephalus. Lumbar CSF galanin determinations, cognitive status, and clinical status were quantified before operation and six months after. Cognition was assessed by an extensive battery of tests measuring attention, memory, speed of mental processing, visuospatial function, and frontal lobe function. Results: CSF galanin concentration decreased after surgery. This reduction correlated with improved clinical and cognitive functioning, specifically with attention and visuomotor speed, visuoconstructive and frontal functioning, and clinical status according to the NPH scale, including the sphincter and cognitive components. Conclusions: The cognitive and clinical improvement after shunt implantation correlated with CSF galanin levels, suggesting that the distribution or function of this agent involves cerebral structures that have some potential for recovery. In this study, galanin was related to several cognitive functions that may be associated with the fronto-subcortical deficits underlying cognitive dysfunction in normal pressure hydrocephalus.

Objective: Although amygdala abnormalities are sometimes suspected in “imaging-negative” patients with video EEG confirmed unilateral focal epilepsy suggestive of temporal lobe epilepsy (TLE), amygdala asymmetry is difficult to assess visually. This study examined a group of “imaging-negative” TLE patients, estimating amygdala volumes, to determine whether cryptic amygdala lesions might be detected. Methods: Review of video EEG monitoring data yielded 11 patients with EEG lateralised TLE and normal structural imaging. Amygdala volumes were estimated in this group, in 77 patients with pathologically verified hippocampal sclerosis (HS), and in 77 controls. Results: Seven of 11 “imaging-negative” cases had both significant amygdala asymmetry and amygdala enlargement, concordant with seizure lateralisation. Although significant amygdala asymmetry occurred in 35 of 77 HS patients, it was never attributable to an abnormally large ipsilateral amygdala. Compared with patients with HS, patients with amygdala enlargement were less likely to have suffered secondarily generalised seizures (p Conclusion: Abnormal amygdala enlargement is reported in seven cases of “imaging-negative” TLE. Such abnormalities are not observed in patients with HS. It is postulated that amygdala enlargement may be attributable to a developmental abnormality or low grade tumour. It is suggested that amygdala volumetry is indicated in the investigation and diagnosis of “imaging-negative” TLE.

Background: The presence of Lewy bodies (LB) in the neocortex and limbic system in patients with Parkinson's disease (PD) is commonly thought to be linked with cognitive impairment. The authors present here a series of patients with diagnosis of PD in life and no significant cognitive impairment who, at necropsy, satisfied the current neuropathological criteria for dementia with Lewy bodies (DLB). Methods: Two hundred and seventy six brains with PD pathology were examined at the Queen Square Brain Bank in London between 1993 and 1999. The neuropathological diagnosis was PD, but 117 patients also had sufficient LB involvement above the brain stem to satisfy the current neuropathological criteria for DLB (50 patients had a neuropathological picture consistent with the limbic category of DLB and 67 with neocortical DLB). Forty eight cases were excluded who developed early cognitive impairment together with motor features of parkinsonism, 12 cases for lack of detailed clinical history, and 19 cases with coexistent features of advanced Alzheimer's disease changes. Thirty eight patients (13.8% of the total with PD pathology and 32.5 % of the total with DLB pathology) were found where there was no or very late cognitive impairment reported in the clinical records. Results: Selected cases were 24 men and 14 women, with a mean (SD) age at onset of parkinsonian symptoms of 60.1 (10.1) years and a mean disease duration of 15.3 (5.5) years. At some time during the evolution of the disease 21 patients developed different degrees of cognitive impairment (after a mean disease duration of 12.2 (4.8) years). Clinical diagnosis at death was PD in 10 cases and PD with dementia in 11. In the remaining 17 patients no history of cognitive impairment was ever recorded in life and all of them had a clinical diagnosis of PD at death; in this subgroup, nine patients later revealed a neuropathological picture consistent with limbic (or transitional) category of DLB and eight with neocortical DLB. Interestingly, in all these patients the parkinsonian features including the response to dopaminergic drugs were indistinguishable from classic brain stem PD. Conclusions: The authors demonstrate that the classic pathology of DLB can commonly be seen outside the generally accepted clinical spectrum for DLB and that important factors other than the absolute number of LB in the neocortex and limbic system influence the development of cognitive impairment in PD. Furthermore, the pathology of PD may be indistinguishable from that reported in DLB, suggesting that the two clinicopathological syndromes may be attributable to the same biological abnormality.

To assess the efficacy of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with advanced Parkinson's disease previously reliant on apomorphine as their main antiparkinsonian medication.Seven patients with motor fluctuations despite optimal medical treatment given as predominantly apomorphine infusion (n=6), or intermittent apomorphine injections (n=1) underwent bilateral STN DBS using frameless stereotactic surgery. Standard assessments of parkinsonism and motor fluctuations, using Unified Parkinson's Disease Rating Scale (UPDRS) were performed before and six months after surgery. Assessments were performed both on and off medication, and postoperative with the stimulators switched on and off.Bilateral STN DBS improved motor scores (UPDRS III) by 61% when off medication (p0.05). Clinical fluctuations (UPDRS IV items 36-39) were reduced by 46.2% (p0.05). Total daily apomorphine dose was reduced by 68.9% (p0.05) and apomorphine infusion via a pump was no longer required in four patients. There were no operative complications. Two patients required treatment for hallucinations postoperatively but there was no significant change in mini-mental state examination.In patients with advanced Parkinson's disease, previously reliant on apomorphine, bilateral STN DBS is an effective treatment to reduce motor fluctuations and enable a reduction in apomorphine use.

Objectives: To test the applicability of an automated method of magnetic resonance image analysis (voxel based morphometry) to detect presence and severity of regional grey matter density reduction—a proxy of atrophy—in Alzheimer's disease. Methods: Twenty nine probable Alzheimer's patients and 26 non-demented controls (mini-mental state examinations mean (SD) 21 (4) and 29 (1)) underwent high resolution 3D brain magnetic resonance imaging. Spatial normalisation to a stereotactic template, segmentation into grey matter, white matter, and cerebrospinal fluid, and smoothing of the grey matter were carried out based on statistical parametric mapping (SPM99) algorithms. Analyses were carried out: (a) contrasting all Alzheimer's patients with all controls (p

Background: Clinical characteristics reminiscent of cerebellar tremor occur in patients with advanced essential tremor. Ballistic movements are known to be abnormal in cerebellar disease. The hypothesis was proposed that ballistic movements are abnormal in essential tremor, reflecting cerebellar dysfunction. Objective: To elucidate the role of the cerebellum in the pathophysiology of essential tremor. Methods: Kinematic parameters and the triphasic electromyographic (EMG) components of ballistic flexion elbow movements were analysed in patients assigned to the following groups: healthy controls (n = 14), pure essential postural tremor (ETPT; n = 17), and essential tremor with an additional intention tremor component (ETIT; n = 15). Results: The main findings were a delayed second agonist burst (AG2) and a relatively shortened deceleration phase compared with acceleration in both the essential tremor groups. These abnormalities were most pronounced in the ETIT group, which had additional prolongation of the first agonist burst (AG1) and a delayed antagonist burst (ANT). Conclusions: Abnormalities of the triphasic pattern and kinematic parameters are consistent with a disturbed cerebellar timing function in essential tremor. These abnormalities were most pronounced in the ETIT group. The cerebellar dysfunction in essential tremor could indicate a basic pathophysiological mechanism underlying this disorder. ETPT and ETIT may represent two expressions within a continuous spectrum of cerebellar dysfunction in relation to the timing of muscle activation during voluntary movements.

To evaluate the hypothesis that the extent of corpus callosum injury indicates the depth of shearing lesions in the central brain structure and therefore relates to the clinical severity of diffuse axonal injury.A simple and objective procedure for semiquantitative analysis of magnetic resonance images (MRI)-the maximum signal intensity ratio (MSIR)-was employed prospectively in 21 patients with diffuse axonal injury but without apparent injury to the ventral pons. All were diagnosed using serial combination MRI scans of fluid attenuated inversion recovery (FLAIR) and T2* weighted gradient echo imaging during the initial two weeks after the injury. The signal intensity ratio between the two regions of interest-the corpus callosum and the normal appearing ventral pons-was calculated serially in mid-sagittal and parasagittal FLAIR image sections in each patient. The MSIR during the study period was determined as a semiquantitative index of corpus callosum injury in each patient. The correlations between MSIR and the duration of unconsciousness, Glasgow outcome scale at six months, and the presence of apparent midbrain injury were investigated.The mean (SD) MSIR value was 1.12 (0.18) at 7.4 (3.1) days after the injury (n = 21). MSIR correlated strongly with the duration of unconsciousness (n = 19, R(2) = 0.74, p0.0001), and was higher in patients with both an unfavourable GOS outcome (p = 0.020) and apparent midbrain injury (p0.001).MSIR, which is a simple and objective procedure for semiquantitative analysis of corpus callosum damage in diffuse axonal injury, correlated with clinical severity. A high MSIR value may indicate the presence of concomitant midbrain injury.

Objective: to analyse 24 parkinsonian patients successfully treated by bilateral STN stimulation for the presence of behavioural disorders. Method: patients were evaluated retrospectively for adjustment disorders (social adjustment scale, SAS), psychiatric disorders (comparison of the results of psychiatric interview and the mini international neuropsychiatric inventory) and personality changes (IOWA scale of personality changes). Results: parkinsonian motor disability was improved by 69.5% and the levodopa equivalent daily dosage was reduced by 60.5%. Social adjustment (SAS) was considered good or excellent in nine patients, moderately (n=14), or severely (n=1) impaired in 15 patients. Psychiatric disorders consisted of amplification or decompensation of previously existing disorders that had sometimes passed unnoticed, such as depressive episodes (n=4), generalised anxiety (n=18), and behavioural disorders with drug dependence (n=2). Appearance of mild to moderate emotional hyperreactivity was reported in 15 patients. Personality traits (IOWA scale) were improved in eight patients, unchanged in seven, and aggravated in eight Conclusion: Improvement in parkinsonian motor disability induced by STN stimulation is not necessarily accompanied by improvement in psychic function and quality of life. Attention is drawn to the possible appearance of personality disorders and decompensation of previous psychiatric disorders in parkinsonian patients who are suitable candidates for neurosurgery. We suggest that a careful psychological and psychiatric interview be performed before surgery, and emphasise the need for psychological follow up to ensure the best possible outcome.

Background: Alzheimer's disease (AD) is characterised by functional impairment, cerebral atrophy, and degeneration of specific neuronal populations, especially pyramidal neurones of the cerebral cortex and hippocampal formation. Although patients with subcortical vascular dementia have been shown to have similar metabolic and volumetric deficits to those with AD, the underlying pathogenesis of these changes is poorly understood. Objective: To determine whether pyramidal cell loss occurs in small vessel disease (SVD) dementia by quantifying hippocampal volume and CA1 neurone number. Methods: Fifty four prospectively studied patients with dementia were screened, and four patients fulfilling criteria for SVD with no other significant neuropathological abnormality were identified. These were compared with five patients fulfilling criteria for AD and seven controls matched for age and sex. The hippocampal formation was serially sectioned, and the number of CA1 pyramidal neurones estimated using the optical dissector technique. Analysis of variance was used to evaluate group differences. Results: Patients in both the AD and SVD groups showed a substantial loss of pyramidal neurones from the CA1 region. The pattern of hippocampal atrophy and the degree of CA1 neuronal loss were similar in the two dementia groups. Conclusions: These findings support recent in vivo studies showing similar metabolic deficits and atrophy in AD and subcortical vascular dementia. In addition, they provide evidence that the underlying cause of these abnormalities is a similar loss of neurones. Whereas the cause of the neuronal loss in AD is related to the deposition of abnormal proteins, the cause in SVD is unknown. In the absence of other pathologies, damage to cerebral microvasculature should be considered a likely candidate.

Objectives: Bilateral chronic high frequency stimulation of the subthalamic nucleus (STN), through the stereotactical placement of stimulating electrodes, effectively improves the motor symptoms of severe Parkinson9s disease. Intraoperative neurophysiological and clinical monitoring techniques (neuronal electrical activity recording and intraoperative stimulation) may improve and refine the localisation of the nucleus. The objective of this work was to compare the preoperative CT and MRI localisation with the intraoperative neurophysiological identification of STN. The relation between the localisation of the STN and the position of the most effective contact of the permanent quadripolar electrode at a 3 month and 1 year follow up was also studied. Methods: Fourteen consecutive parkinsonian patients were submitted to bilateral implant for STN stimulation. All the patients underwent a standard MRI and stereotactic CT to obtain, by image fusion and localisation software, the stereotactical coordinates of STN. The STN extension and boundaries were identified by a semimicrorecording of the neuronal electrical activity. The definitive quadripolar electrode was positioned to locate at least two contacts within the STN recording area. Intraoperative macrostimulation was performed to confirm the correct position of the electrode. Postoperative clinical evaluation of the effects of stimulation was checked for each contact of the quadripolar electrode testing the improvement on contralateral rigidity to select the best contact. This evaluation was repeated at 3 months and 1 year after surgery. Results: In 35.7% of the procedures it was necessary to perform more than one track to get a recording of neuronal activity consistent with STN. The mean position of the central point of all the 28 STN recording areas in respect of the AC-PC line midpoint was 2.7 mm posterior (SD 0.7), 3.8 mm inferior (SD 1.1), and 11.6 mm lateral (SD 0.9), and the mean distance between the anatomical target and the central point of the STN as defined by intraoperative recording was 0.5 mm (SD 0.5) on the anteroposterior plane, 0.7 mm (SD 0.7) on the lateral plane, and 0.9 mm (SD 0.6) on the vertical plane. At 1 year the mean position of the central point of the most effective contact of the electrode in respect of the AC-PC line midpoint was 1.7 mm posterior (SD 0.9), 1.7 mm inferior (SD 1.5), and 12.3 mm lateral (SD 0.9). Conclusion: The results highlight the role of the intraoperative recording to get a more accurate localisation of the STN in surgery for Parkinson9s disease, allowing the identification of the boundaries and of the extension of the nucleus. The most effective contact of the quadripolar electrode was always in the upper part of the STN recording area or immediately above it, suggesting a role of this region in the clinical effectiveness of the STN electrical stimulation.

Possible mechanisms by which the intestinal contents may influence afferent nerve fibres in the lamina propria of the intestinal mucosa are discussed in this brief review. After addressing intestinal epithelial permeability, endocrine and brush cells are discussed, as well as enterocytes, as sensors for luminal microbes.

The fossil record indicates that early mammals had small brains with proportionately little neocortex. Here we consider what is known about the organization of the neocortex in species with the least expanded neocortex from 6 major clades of the mammalian radiation. Common features of the neocortex across these clades include primary and secondary sensory areas, retrosplenial and cingulate cortex, and frontal cortex. Overall, early mammals likely had a core of 15–20 cortical areas that have been retained in most present-day mammals.

Biologists have long been interested in both the regularities and the deviations in the relationship between brain, development, ecology, and behavior between taxa. We first examine some basic information about the observed ranges of fundamental changes in developmental parameters (i.e. neurogenesis timing, cell cycle rates, and gene expression patterns) between taxa. Next, we review what is known about the relative importance of different kinds of developmental mechanisms in producing brain change, focusing on mechanisms of segmentation, local and general features of neurogenesis, and cell cycle kinetics. We suggest that a limited set of developmental alterations of the vertebrate nervous system typically occur and that each kind of developmental change may entail unique anatomical, functional, and behavioral consequences for the organism. Thus, neuroecologists who posit a direct mapping of brain size to behavior should consider that not any change in brain anatomy is possible.

Traumatic brain injury (TBI) in infants and children remains a public health problem of enormous magnitude. It is a complex and heterogeneous condition that presents many diagnostic, therapeutic and prognostic challenges. A number of investigative teams are studying pediatric TBI both in experimental models and in clinical studies at the bedside. This review builds on work presented in a prior supplement to Developmental Neuroscience that was published in 2006, and addresses several active areas of research on this topic, including (1) the application of novel imaging methods, (2) the use of serum and/or CSF biomarkers of injury, (3) advances in neuromonitoring, (4) the development and testing of novel therapies, (5) developments in modeling pediatric TBI, (6) the consideration of a new approach to classification of pediatric TBI, and (7) assessing the potential impact of the development of pediatric and neonatal neurocritical care services on the management and outcome of pediatric TBI.

Background: 123 I-labelled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ( 123 I-FP-CIT) imaging is a diagnostic tool to help differentiate dementia with Lewy bodies (DLB) from Alzheimer’s disease (AD). However, in animals, cholinesterase inhibitors (ChEi) have been reported to reduce radioligand binding to the striatal dopamine transporter. As ChEi are frequently used in people with dementia, it is important to determine whether their use affects 123 I-FP-CIT uptake in the striatum. Objective: To clarify whether chronic ChEi therapy modulates striatal dopamine transporter binding measured by 123 I-FP-CIT in patients with AD, DLB and Parkinson’s disease with dementia (PDD). Design: Cross sectional study in 99 patients with AD (nine on ChEi, 25 not on ChEi), DLB (nine on ChEi, 19 not on ChEi) and PDD (six on ChEi, 31 not on ChEi) comparing 123 I-FP-CIT striatal binding (caudate, anterior and posterior putamen) in patients receiving compared with those not receiving ChEi, correcting for key clinical variables including diagnosis, age, sex, Mini-Mental State Examination score, severity of parkinsonism and concurrent antidepressant use. Results: As previously described, 123 I-FP-CIT striatal uptake was lower in DLB and PDD subjects compared with those with AD. Median duration of ChEi use was 180 days. 123 I-FP-CIT uptake was not significantly reduced in subjects receiving ChEi compared those not receiving ChEi (mean percentage reduction: AD 4.3%; DLB 0.7%; PDD 6.1%; p = 0.40). ChEi use did not differentially affect striatal 123 FP-CIT uptake between patient groups (p = 0.83). Conclusions: Use of ChEi does not significantly influence the ability of 123 I-FP-CIT imaging to distinguish AD from DLB.

Conventional MRI can provide critical information for care of patients with traumatic brain injury (TBI), but MRI abnormalities rarely correlate to clinical severity and outcome. Previous magnetic resonance spectroscopy studies have reported clinically relevant brain metabolic changes in patients with TBI. However, these changes were often assessed a few to several days after the trauma, with a consequent variation of the metabolic pattern due to temporal changes.Proton magnetic resonance spectroscopic imaging (1H-MRSI) examinations were performed in 10 patients with TBI 48-72 h after the trauma, to obtain early measurements of central brain levels of N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and lactate (La). Metabolite values were expressed as ratios to (1) a metabolic pattern, given by the sum of the resonance intensities of all metabolites detected in the same voxel and (2) intravoxel Cr.NAA ratios were found to be significantly lower in patients with TBI than in normal controls. In contrast, Cho ratios were significantly higher in patients with TBI than in normal controls. Increased La levels were found in 5 of 10 patients with TBI. Both NAA and La values correlated closely with those of the Glasgow Coma Scale at presentation (r = 0.73 and -0.62, respectively; p0.01 for both) and the Glasgow Outcome Scale at 3 months (r = -0.79 and 0.79, respectively; p0.01 for both).Spectroscopic measures of neuro-axonal damage occurring soon after a brain trauma are clinically relevant. Significant increases in cerebral La level also may be detected when 1H-MRSI is performed early after the trauma and, at this stage, can represent a reliable index of injury severity and disease outcome in patients with TBI.