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Since 1877 Brain has always provided researchers and clinicians with the finest original contributions in neurology. Its citation rating has been one of the highest for neurology journals and it has consistently published papers which have become classics in the field. Leading studies in neurological science are balanced with practical clinical articles and because all papers are submitted on disk we've shortened our production time so you can read the best research as it happens without delay. The editorial board reflects both the journal's truly international readership and wider coverage.

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Oxford University Press

Publications in this journal

• Live imaging of Toll-like receptor 2 response in cerebral ischaemia reveals a role of olfactory bulb microglia as modulators of inflammation.

  Authors: Lalancette-Hébert M, Phaneuf D, Soucy G, Weng YC, Kriz J

  Brain. 132(4-doi: 10.1093/brain/awn345):940-54.

  Activation of microglial cells in response to ischaemic injury, inflammatory and/or immune stimuli is associated with the marked induction of Toll-like receptor 2 (TLR2). At present, little is knownActivation of microglial cells in response to ischaemic injury, inflammatory and/or immune stimuli is associated with the marked induction of Toll-like receptor 2 (TLR2). At present, little is known about the spatial and temporal sequence of events, micro-regional specificities and the potential long term role of the TLR2 response to brain injuries. To investigate microglial activation/TLR2 response in real time, we generated a transgenic mouse model bearing the dual reporter system luciferase/green fluorescent protein under transcriptional control of a murine TLR2 promoter. In this model, transcriptional activation of TLR2 was visualized in the brains of live animals using biophotonic/bioluminescence molecular imaging and a high resolution/sensitivity charged coupled device camera. It was found that TLR2 induction/microglial activation has a marked chronic component after ischaemic injury and may last several months after the initial attack. The pro-inflammatory response was not restricted to the site of ischaemic injury but was also evident in the olfactory bulb. A significant TLR2 response was first seen in the olfactory bulb 6 h after stroke and several hours before the increase in photon emission over the site of infarction. This sequence of events was further confirmed by immunohistochemistry. A similar early TLR2 response from olfactory bulb microglia was observed in the brain's immune response to pathogens. We therefore propose that, owing to their unique situation, receiving and translating numerous inputs from the brain as well as from the environment, olfactory bulb microglia may serve as sensors and/or modulators of brain inflammation.

• Changes in spinal cord architecture after brachial plexus injury in the newborn.

  Authors: Klaus J Korak, Siu Lin Tam, Tessa Gordon, Manfred Frey, Oskar C Aszmann

  Brain : a journal of neurology. 127(Pt 7):1488-95.

  Obstetric brachial plexus palsy is a devastating birth injury. While many children recover spontaneously, 20-25% are left with a permanent impairment of the affected limb. So far, concepts ofObstetric brachial plexus palsy is a devastating birth injury. While many children recover spontaneously, 20-25% are left with a permanent impairment of the affected limb. So far, concepts of pathology and recovery have focused on the injury of the peripheral nerve. Proximal nerve injury at birth, however, leads to massive injury-induced motoneuron loss in corresponding motoneuron pools and therefore limits the extent of functional recovery. In the present study, the role of spinal cord plasticity after injury and recovery from obstetric brachial plexus lesions was investigated. A selective injury to spinal roots C5 and C6 was induced in newborn Sprague-Dawley rats, leading to motoneuron loss in corresponding motoneuron pools. Recovery of extremity function was evaluated with different behavioural paradigms. Permanent changes of adjacent motoneuron pools were quantitatively evaluated by retrograde tracing and functional muscle testing. We report that the adjacent C7 motoneuron contribution to biceps muscle innervation increased four-fold after upper trunk lesions in newborns, thus compensating for the injury-induced motoneuron loss. These results indicate that, in obstetric brachial plexus palsy, changes in spinal cord architecture are an integral part not only of primary pathology but also of the subsequent recovery process. While present treatment is directed towards the restoration of neural continuity, future treatment strategies must recognize and take advantage of CNS participation in the injury and recovery process.

• Development of biomarkers in multiple sclerosis.

  Authors: Bibiana Bielekova, Roland Martin

  Brain : a journal of neurology. 127(Pt 7):1463-78.

  Multiple sclerosis is a complex disease, as several pathophysiological processes (including inflammation, demyelination, axonal damage and repair mechanisms) participate in the disease process.Multiple sclerosis is a complex disease, as several pathophysiological processes (including inflammation, demyelination, axonal damage and repair mechanisms) participate in the disease process. Furthermore, as new pathological evidence reveals, these processes are not uniformly represented across patient populations but can selectively predominate in individual patients, thus contributing to the heterogeneity in phenotypic expression of the disease, its prognosis and response to therapies. While the armamentarium of available therapies for multiple sclerosis broadens, little is known about factors that predict treatment response in individual patients to a specific drug. More importantly, we are beginning to understand that, analogous to cancer therapy, the successful therapeutic strategy in multiple sclerosis might ultimately involve the combination of different therapeutics targeting several dominant pathophysiological processes. The development of these process-specific therapies will be impossible without the use of biomarkers that reflect the targeted process, can select patient population in which the targeted process is prevailing and can aid during the more rapid screening of therapeutic agents in the early phase of their development. This review summarizes the general concepts of biomarkers and their potential use as surrogate endpoints and tailors these concepts to specific applications in multiple sclerosis research.

• Word retrieval in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study.

  Authors: S Abrahams, L H Goldstein, A Simmons, M Brammer, S C R Williams, V Giampietro, P N Leigh

  Brain : a journal of neurology. 127(Pt 7):1507-17.

  The cognitive impairment revealed in some non- demented amyotrophic lateral sclerosis (ALS) patients is characterized by executive dysfunction with widely repeated deficits on tests of verbalThe cognitive impairment revealed in some non- demented amyotrophic lateral sclerosis (ALS) patients is characterized by executive dysfunction with widely repeated deficits on tests of verbal (letter) fluency. However, conflicting evidence exists of an impairment on other word retrieval tasks, such as confrontation naming, which do not place heavy demands on executive processes. Previous research has demonstrated intact confrontation naming in the presence of verbal fluency deficits, although naming deficits have been described in other studies. In this investigation, functional MRI (fMRI) techniques were employed to explore whether word retrieval deficits and underlying cerebral abnormalities were specific to letter fluency, which are more likely to indicate executive dysfunction, or were also present in confrontation naming, indicating language dysfunction. Twenty-eight non-demented ALS patients were compared with 18 healthy controls. The two groups were matched for age, intelligence quotient, years of education, and anxiety and depression scores. Two compressed-sequence overt fMRI activation paradigms were employed, letter fluency and confrontation naming, which were developed for use with an older and potentially impaired population. In ALS patients relative to controls, the letter fluency fMRI task revealed significantly impaired activation in the middle and inferior frontal gyri and anterior cingulate gyrus, in addition to regions of the parietal and temporal lobes. The confrontation naming fMRI task also revealed impaired activation in less extensive prefrontal regions, including the inferior frontal gyrus and regions of the temporal, parietal and occipital lobes. These changes were present despite matched performance between patients and controls during each activation paradigm. The pattern of dysfunction corresponded to the presence of cognitive deficits on both letter fluency and confrontation naming in the ALS group. This study provides evidence of cerebral abnormalities in ALS in the network of regions involved in language and executive functions. Moreover, the findings further illustrate the heterogeneity of cognitive and cerebral change in ALS.

• The impact of early and late damage to the human amygdala on 'theory of mind' reasoning.

  Authors: P Shaw, E J Lawrence, C Radbourne, J Bramham, C E Polkey, A S David

  Brain : a journal of neurology. 127(Pt 7):1535-48.

  There is a burgeoning interest in the neural basis of the ability to attribute mental states to others; a capacity referred to as 'theory of mind' (ToM). We examined the effects of lesions of theThere is a burgeoning interest in the neural basis of the ability to attribute mental states to others; a capacity referred to as 'theory of mind' (ToM). We examined the effects of lesions of the amygdala which arise at different stages of development on this key aspect of social cognition. Tests of ToM, executive and general neuropsychological function were given to subjects with lesions of the amygdala arising congenitally or in early childhood ('early damage', n = 15), subjects who acquired damage to the amygdala in adulthood ('late damage' n = 11) and matched clinical (n = 14) and healthy comparison groups (n = 38). Subjects with early damage to the amygdala, particularly if the lesion was associated with childhood onset of seizures, were impaired relative to all other groups on more advanced tests of ToM reasoning, such as detecting tactless or ironic comments or interpreting non-literal utterances. These deficits held for subjects with either left or right early amygdala damage and encompassed the understanding of both the beliefs and emotional states of others. In contrast, subjects who acquired damage to the amygdala in adulthood (usually as part of an anterior temporal lobectomy) were not impaired in ToM reasoning relative to both clinical and healthy controls, supporting the position that the amygdala is not part of the neural circuitry mediating the 'on-line' performance of ToM reasoning. In line with theories which claim that ToM is an independent faculty of cognition, we found that the pattern of results held after co-varying for measures of executive function, memory and general intellectual functioning. We discuss the results in the light of recent theories which link early developmental insults to the amygdala with the ToM impairments which are thought to be a core neurocognitive deficit found in disorders such as autism. We conclude that the amygdala may play an important role in the neural systems supporting the normal development of ToM reasoning.

• Vestibular-evoked muscle responses in patients with spinal cord injury.

  Authors: J F Iles, Alima S Ali, Gordana Savic

  Brain : a journal of neurology. 127(Pt 7):1584-92.

  The vestibular system was activated by galvanic electrical stimulation in 22 patients with spinal cord injury. Three patients were studied standing and all were studied sitting. ElectromyographicThe vestibular system was activated by galvanic electrical stimulation in 22 patients with spinal cord injury. Three patients were studied standing and all were studied sitting. Electromyographic responses recorded in soleus (standing patients) and the erectores spinae (all patients) were compared with data from 18 control subjects. The vestibular stimulus polarity and head position were arranged so as to produce excitatory medium latency muscle responses in the controls. Responses in the patient group were present bilaterally, present unilaterally or absent below the level of injury. The amplitude of response recorded in erectores spinae at lumbar levels below the lesion in 21 patients (left and right side responses summed) and five control subjects was positively correlated with American Spinal Injuries Association (ASIA) grade: the smallest amplitudes were found in patients with the most severe impairment (Spearman rank correlation coefficient rs = 0.59; P = 0.002, two-tailed). The latency of response (averaged for both sides) was negatively correlated with ASIA grade in 21 patients: the longest latencies were found in patients with the most severe impairment (rs = -0.57; P < 0.01, two-tailed). Amplitude and latency were negatively correlated (rs = -0.72, P < 0.002, two-tailed). The latencies of responses recorded in the erectores spinae at different vertebral levels were linearly related to the vertical distance from the inion to the recording site in both patient and control groups. The conduction velocities of the spinal pathways activated by vestibular stimulation were 4.6 and 10.4 m/s in patient (recording below lesion) and control groups, respectively. Both clinical status (patients recording below lesion, patients recording above lesion and controls) and distance were significant predictors of latency (general linear model, P < 0.0005). It is concluded that measurement of vestibular-evoked responses could provide information on the level and density of spinal cord lesions.

• The time course of epidermal nerve fibre regeneration: studies in normal controls and in people with diabetes, with and without neuropathy.

  Authors: Michael Polydefkis, Peter Hauer, Soham Sheth, Michael Sirdofsky, John W Griffin, Justin C McArthur

  Brain : a journal of neurology. 127(Pt 7):1606-15.

  We sought to develop and validate a standardized cutaneous nerve regeneration model and to define the rate of epidermal nerve fibre (ENF) regeneration first in healthy control subjects and then inWe sought to develop and validate a standardized cutaneous nerve regeneration model and to define the rate of epidermal nerve fibre (ENF) regeneration first in healthy control subjects and then in neuropathic and neuropathy-free subjects with diabetes. Next, we assessed the effect of different factors on the rate of nerve fibre regeneration and investigated whether such an approach might offer insight into novel trial designs and outcome measures. All subjects had a standardized topical capsaicin dressing applied to the distal lateral thigh. ENF densities derived from skin biopsies were determined at baseline, after capsaicin treatment and at reinnervation time points. For each subject, the best fit line from post-denervation data was determined and the slope was used as the rate of regeneration. In healthy control subjects, regeneration was correlated with psychophysical sensory testing, electron microscopy studies and immunohistochemistry with alternative axonal membrane markers. Topical capsaicin application produced complete or nearly complete denervation of the epidermis in both control subjects and people with diabetes. The rate of regeneration was associated with the baseline ENF density (P < 0.001), but not age (P = 0.75), gender (P = 0.18), epidermal thickness (P = 0.4) or post-capsaicin treatment density (P = 0.7). ENF regeneration, as determined by recovery of ENF density, occurred at a rate of 0.177 +/- 0.075 fibres/mm/day in healthy control subjects and was significantly reduced in subjects with diabetes (0.074 +/- 0.064, P < 0.001) after adjusting for changes in baseline ENF density. Among subjects with diabetes, the presence of neuropathy was associated with a further reduction in regenerative rate (0.10 +/- 0.07 versus 0.04 +/- 0.03, P = 0.03), though diabetes type (P = 0.7), duration of diabetes (P = 0.3) or baseline glycated haemoglobin (P = 0.6) were not significant. These results have several implications. First, topical capsaicin application can produce a uniform epidermal nerve fibre injury that is safe and well tolerated, and offers an efficient strategy to measure and study nerve regeneration in man. Secondly, using our techniques, reduced rates of nerve regeneration were found in people with diabetes without evidence of neuropathy and indicate that abnormalities in peripheral nerve function are present early in diabetes, before signs or symptoms develop. These results suggest that regenerative neuropathy trials could include non-neuropathic subjects and that trial duration can be dramatically shortened.

• Right temporal cortex is critical for utilization of melodic contextual cues in a pitch constancy task.

  Authors: Catherine M Warrier, Robert J Zatorre

  Brain : a journal of neurology. 127(Pt 7):1616-25.

  Pitch constancy, perceiving the same pitch from tones with differing spectral shapes, requires one to extract the fundamental frequency from two sets of harmonics and compare them. We previouslyPitch constancy, perceiving the same pitch from tones with differing spectral shapes, requires one to extract the fundamental frequency from two sets of harmonics and compare them. We previously showed this difficult task to be easier when tonal context is present, presumably because the context creates a tonal reference point from which to judge the test tone. The present study assessed the role of the right auditory cortex in using tonal context for pitch judgements. Thirty-six patients with focal brain excisions of the right or left anterior temporal lobe (RT, LT) and 12 matched control participants (NC) made pitch judgements on complex tones that could differ in fundamental frequency and/or spectral shape. This task was performed in isolation and within a melodic context. The RT group showed impairments both on trials in which extraction of pitch from differing spectral shapes was required (different-timbre trials) and when this was not required (same-timbre trials). All groups performed poorly in the isolated condition, but improved with melodic context. Degree of improvement varied in that the LT group performed normally, whereas the RT group was not able to obtain the same amount of facilitation from the melodic context. In particular, melodic context did not facilitate the RT group's performance on different-timbre trials. Excisions within Heschl's gyrus did not affect these results, suggesting that the impairments were due to the removal of the anterior temporal cortex. The results of this study therefore implicate right anterior auditory cortical areas in making pitch judgements relative to tones that were heard previously. We propose that auditory association areas located on the anterior portion of the superior temporal gyrus, an area with connections to frontal regions implicated in working memory, could be involved in holding and integrating tonal information.

• In vivo MRI of brain inflammation in human ischaemic stroke.

  Authors: Andreas Saleh, Michael Schroeter, Cornelia Jonkmanns, Hans-Peter Hartung, Ulrich Mödder, Sebastian Jander

  Brain : a journal of neurology. 127(Pt 7):1670-7.

  Inflammation contributes to brain damage caused by ischaemic stroke. Macrophages, as the prevailing inflammatory cell population in stroke lesions, can be visualized using ultrasmallInflammation contributes to brain damage caused by ischaemic stroke. Macrophages, as the prevailing inflammatory cell population in stroke lesions, can be visualized using ultrasmall superparamagnetic iron oxide (USPIO) as a cell-specific contrast agent for MRI. In this single-centre open-labelled clinical phase II study we tested the potential of USPIO-enhanced MRI for macrophage imaging in human ischaemic stroke lesions. In a series of 10 consecutive patients, USPIO contrast agent was infused at the end of the first week after symptom onset. Two follow-up MRI scans were performed 24-36 h and 48-72 h after infusion. Two distinct components of USPIO-related signal changes were discernible, one associated with blood vessels and one representing parenchymal enhancement. Vessel-associated changes appeared as signal loss on T2/T2*-weighted images and decreased from the first to second scan after USPIO infusion, most likely reflecting a transient blood pool effect of the contrast agent. Conversely, parenchymal enhancement was mainly evident on T1-weighted images, increased over time, and matched with the expected distribution of macrophages. Importantly, USPIO-induced signal alterations throughout differed from signatures of conventional gadolinium-enhanced MRI, thus being independent from breakdown of the blood-brain barrier. We suggest that increasing USPIO-enhancement on T1-weighted images indicates brain infiltration by USPIO-laden macrophages. Thus, USPIO-enhanced MRI may provide an in vivo surrogate marker of cellular inflammation in stroke and other CNS pathologies.

• Familial clustering and genetic risk for dementia in a genetically isolated Dutch population.

  Authors: K Sleegers, G Roks, J Theuns, Y S Aulchenko, R Rademakers, M Cruts, W A van Gool, C Van Broeckhoven, P Heutink, B A Oostra, J C van Swieten, C M van Duijn

  Brain : a journal of neurology. 127(Pt 7):1641-9.

  Despite advances in elucidating the genetic epidemiology of Alzheimer's disease and frontotemporal dementia, the aetiology for most patients with dementia remains unclear. We examined the geneticDespite advances in elucidating the genetic epidemiology of Alzheimer's disease and frontotemporal dementia, the aetiology for most patients with dementia remains unclear. We examined the genetic epidemiology of dementia in a recent genetically isolated Dutch population founded around 1750. The series of 191 patients ascertained comprised 122 probable Alzheimer's disease patients with late onset and 17 with early onset, and 22 with possible Alzheimer's disease. It further included 10 patients with vascular dementia, nine with Lewy body dementia and six with frontotemporal dementia. All patients, except those with vascular dementia, were more closely related than healthy individuals from the same area. Clustering was strongest for patients with early-onset Alzheimer's disease or Lewy body dementia. Although 14% of late-onset Alzheimer's disease patients had evidence of autosomal dominant disease, consanguinity was found in three late-onset Alzheimer's disease patients, suggesting a recessive or polygenic model underlying the trait. We found no clustering of vascular dementia, implying a difference in genetic risk for late-onset Alzheimer's disease and vascular dementia. Mutations in known genes could not explain the occurrence of dementia, but the population attributable proportion of apolipoprotein E gene (APOE*4) was high (45%) due to a high frequency of APOE*4 carriers. Earlier identified regions on chromosomes 10 and 12, nor the effect of the alpha-2-macroglobulin (A2M) I/D polymorphism on Alzheimer's disease could be confirmed in our study. We did find evidence for association between the A2M D-allele and Lewy body dementia. Our data showed a strong familial clustering of various forms of dementia in this isolated Dutch population. A high percentage of late-onset Alzheimer's disease could be explained by APOE*4, but 55% of its origin is still unknown.

• A componential analysis of task-switching deficits associated with lesions of left and right frontal cortex.

  Authors: Adam R Aron, Stephen Monsell, Barbara J Sahakian, Trevor W Robbins

  Brain : a journal of neurology. 127(Pt 7):1561-73.

  Executive functions such as task-set switching are thought to depend on the frontal cortex. However, more precision is required in identifying which components of such high-level processes relate toExecutive functions such as task-set switching are thought to depend on the frontal cortex. However, more precision is required in identifying which components of such high-level processes relate to which, if any, subregions of the brain. In a recent study of 19 patients with focal right frontal (RF) lesions and 17 with left frontal (LF) lesions, we found that response inhibition, as measured by the stop-signal task, was specifically disrupted by damage to the right inferior frontal gyrus (IFG). The present study examined task-switching performance in this same group of patients and in matched controls on the grounds that inhibitory mechanisms may also be required to switch task-set. Both RF and LF patients showed significantly larger switch costs (the difference, in reaction time and errors, between changing tasks and repeating the same task) than controls, but apparently for different reasons. For RF patients, a part of the switch deficit could be accounted for by impaired inhibition of inappropriate responses or task-sets triggered by stimuli, and one measure of the switch cost correlated reliably with damage to the IFG, specifically the pars opercularis (POp). For LF patients, a part of the switch deficit may have arisen from weak top-down control of task-set. The degree of top-down control correlated reliably with the extent of damage to the left middle frontal gyrus (MFG). This study localizes two components of the complex task-switching process (inhibition of task-sets and/or responses and top-down control of task-set) to the right IFG/POp and the left MFG respectively.

• 'In the course of time': a PET study of the cerebral substrates of autobiographical amnesia in Alzheimer's disease.

  Authors: Francis Eustache, Pascale Piolino, Bénédicte Giffard, Fausto Viader, Vincent de la Sayette, Jean-Claude Baron, Béatrice Desgranges

  Brain : a journal of neurology. 127(Pt 7):1549-60.

  Neuroimaging studies in healthy subjects have yielded controversial results about the neural substrates of autobiographical memory. Moreover, the neural networks responsible for autobiographicalNeuroimaging studies in healthy subjects have yielded controversial results about the neural substrates of autobiographical memory. Moreover, the neural networks responsible for autobiographical amnesia remain poorly understood. Since autobiographical memory is frequently altered in Alzheimer's disease (AD), we used this degenerative disorder as a model and applied a correlative approach between resting cerebral glucose utilization (CMRGlc) and temporally graded memory scores to identify the cerebral structures whose synaptic dysfunction subserves the impairment in autobiographical memory. To this end, we studied a group of 17 AD patients with mild to moderate dementia in whom autobiographical memory was assessed using a specially designed task from three broad time periods [the previous 5 years (period A); middle age (period B); and teenage and childhood (period C)], and measures of resting CMRGlc were obtained with PET. The patients performed less well than a control group for all three time periods and showed the expected temporal gradient, with the most remote period being best preserved (Ribot's gradient). Qualitative analysis showed that remote memories concerned generic (i.e. semantic) rather than specific (i.e. episodic) events. We found a significant positive correlation between autobiographical scores and the metabolism of the right hippocampus (extending to the lingual gyrus), restricted to period A. In addition, period A scores were significantly correlated with the right middle and inferior frontal gyri and the right middle temporal gyrus. Period B scores correlated chiefly with the prefrontal cortex bilaterally (bilateral superior, bilateral middle and right inferior gyri). Metabolic correlations with period C scores were restricted to the left middle frontal gyrus. These findings show striking differences in metabolic correlations with the autobiographical time period, in agreement with prevalent theories of normal functioning of human memory. Thus, in accordance with theories of long-term memory consolidation, we find the expected implication of the hippocampal region in the recall of recent memories, and a disengagement of this structure when the retention interval is beyond 5 years. Moreover, according to the hemispheric encoding/retrieval asymmetry model based on activation studies in healthy subjects, the fact that recent memories preferentially involved the right prefrontal cortex whereas remote memories involved the left prefrontal cortex supports the notion of semanticization of memories with time interval, such that preserved remote memories in AD have a predominantly semantic character.

• Cholinergic enhancement of frontal lobe activity in mild cognitive impairment.

  Authors: Andrew J Saykin, Heather A Wishart, Laura A Rabin, Laura A Flashman, Tara L McHugh, Alexander C Mamourian, Robert B Santulli

  Brain : a journal of neurology. 127(Pt 7):1574-83.

  Cholinesterase inhibitors positively affect cognition in Alzheimer's disease (AD) and other conditions, but no controlled functional MRI studies have examined where their effects occur in the brain.Cholinesterase inhibitors positively affect cognition in Alzheimer's disease (AD) and other conditions, but no controlled functional MRI studies have examined where their effects occur in the brain. We examined the effects of donepezil hydrochloride (Aricept) on cognition and brain activity in patients with amnestic mild cognitive impairment (MCI), a diagnosis associated with a high risk of developing AD. Nine older adults with MCI were compared with nine healthy, demographically matched controls. At baseline, patients showed reduced activation of frontoparietal regions relative to controls during a working memory task. After stabilization on donepezil (5.7 +/- 1.7 weeks at 10 mg) patients showed increased frontal activity relative to unmedicated controls, which was positively correlated with improvement in task performance (r = 0.49, P = 0.05) as well as baseline hippocampal volume (r = 0.62, P < 0.05). The patients' overall cognitive function was stable or improved throughout the study. Short-term treatment with a cholinesterase inhibitor appears to enhance the activity of frontal circuitry in patients with MCI, and this increase appears to be related to improved cognition and to baseline integrity of the hippocampus. These relationships have implications for understanding the mechanisms by which cognition-enhancing medications exert their effects on brain function and for the use of functional MRI in early detection and treatment monitoring of AD and MCI.

• High-frequency oscillations and seizure generation in neocortical epilepsy.

  Authors: Greg A Worrell, Landi Parish, Stephen D Cranstoun, Rachel Jonas, Gordon Baltuch, Brian Litt

  Brain : a journal of neurology. 127(Pt 7):1496-506.

  Neocortical seizures are often poorly localized, explosive and widespread at onset, making them poorly amenable to epilepsy surgery in the absence of associated focal brain lesions. We describe, forNeocortical seizures are often poorly localized, explosive and widespread at onset, making them poorly amenable to epilepsy surgery in the absence of associated focal brain lesions. We describe, for the first time in an unselected group of patients with neocortical epilepsy, the finding that high-frequency (60-100 Hz) epileptiform oscillations are highly localized in the seizure onset zone, both before and temporally removed from seizure onset. These findings were observed in all six patients with neocortical epilepsy out of 23 consecutive patients implanted with intracranial electrodes for pre-surgical evaluation during the study period. The majority of seizures (62%) in these patients were anticipated by an increase in high-frequency activity in the 20 min prior to neocortical seizure onset. Contrary to observations in normal brain, high-frequency activity was strongly modulated by behavioural state, and was maximal during slow-wave sleep, which may explain the propensity for neocortical onset seizures to begin during sleep. These findings point to an important role for neuromodulatory circuits, probably involving the thalamus, in mechanisms underlying seizure generation in neocortical epilepsy. These findings demonstrate that high-frequency epileptiform oscillations may prove clinically useful in localizing the seizure onset zone in neocortical epilepsy, for identifying periods of increased probability of seizure onset, and in elucidating mechanisms underlying neocortical ictogenesis. Confirmation that prolonged bursts of high-frequency activity may predict focal onset neocortical seizures will require prospective validation on continuous, prolonged recordings in a larger number of patients. Importantly, the results show that the dynamic range utilized in current clinical practice for localization of epileptogenic brain largely ignores fundamental oscillations that are signatures of an epileptogenic brain. It may prove that many currently available clinical EEG systems and EEG analysis methods utilize a dynamic range that discards clinically important information.

• Therapeutic doses of L-dopa reverse hypersensitivity of corticostriatal D2-dopamine receptors and glutamatergic overactivity in experimental parkinsonism.

  Authors: Barbara Picconi, Diego Centonze, Silvia Rossi, Giorgio Bernardi, Paolo Calabresi

  Brain : a journal of neurology. 127(Pt 7):1661-9.

  Levodopa (l-dopa) therapy is still considered the gold-standard in the treatment of Parkinson's disease. However, the synaptic and cellular mechanisms involved in the amelioration of motor symptomsLevodopa (l-dopa) therapy is still considered the gold-standard in the treatment of Parkinson's disease. However, the synaptic and cellular mechanisms involved in the amelioration of motor symptoms during this treatment are still unclear. To address this issue, we analysed the physiological and pharmacological properties of striatal glutamatergic and GABAergic synaptic transmission in an experimental model of Parkinson's disease. Single-cell recordings were performed in sham-operated rats, in 6-hydroxydopamine-lesioned animals and in rats receiving chronic l-dopa treatment following dopamine (DA) denervation. We utilized a dose of l-dopa (10 mg/kg, twice daily for 21 days) able to reverse motor deficits in about half of parkinsonian animals. In the striatum of parkinsonian animals showing therapeutic benefits following l-dopa treatment, we observed a reversal of glutamatergic overactivity and of the hypersensitivity of presynaptic D2 DA receptors controlling glutamate release from corticostriatal terminals. Conversely, no change was detected in the sensitivity of presynaptic D2 DA receptors modulating striatal GABA transmission in both parkinsonian and l-dopa-treated rats. We suggest that the reversal of striatal glutamatergic overactivity and the normalization of hypersensitive D2 DA receptors modulating excitatory transmission might underlie some of the therapeutic actions of l-dopa in Parkinson's disease.

• GABAA receptor-dependent synchronization leads to ictogenesis in the human dysplastic cortex.

  Authors: M D'Antuono, J Louvel, R Köhling, D Mattia, A Bernasconi, A Olivier, B Turak, A. Devaux, R Pumain, M Avoli

  Brain : a journal of neurology. 127(Pt 7):1626-40.

  Patients with Taylor's type focal cortical dysplasia (FCD) present with seizures that are often medically intractable. Here, we attempted to identify the cellular and pharmacological mechanismsPatients with Taylor's type focal cortical dysplasia (FCD) present with seizures that are often medically intractable. Here, we attempted to identify the cellular and pharmacological mechanisms responsible for this epileptogenic state by using field potential and K+-selective recordings in neocortical slices obtained from epileptic patients with FCD and, for purposes of comparison, with mesial temporal lobe epilepsy (MTLE), an epileptic disorder that, at least in the neocortex, is not characterized by any obvious structural aberration of neuronal networks. Spontaneous epileptiform activity was induced in vitro by applying 4-aminopyridine (4AP)-containing medium. Under these conditions, we could identify in FCD slices a close temporal relationship between ictal activity onset and the occurrence of slow interictal-like events that were mainly contributed by GABAA receptor activation. We also found that in FCD slices, pharmacological procedures capable of decreasing or increasing GABAA receptor function abolished or potentiated ictal discharges, respectively. In addition, the initiation of ictal events in FCD tissue coincided with the occurrence of GABAA receptor-dependent interictal events leading to [K+]o elevations that were larger than those seen during the interictal period. Finally, by testing the effects induced by baclofen on epileptiform events generated by FCD and MTLE slices, we discovered that the function of GABAB receptors (presumably located at presynaptic inhibitory terminals) was markedly decreased in FCD tissue. Thus, epileptiform synchronization leading to in vitro ictal activity in the human FCD tissue is initiated by a synchronizing mechanism that paradoxically relies on GABAA receptor activation causing sizeable increases in [K+]o. This mechanism may be facilitated by the decreased ability of GABAB receptors to control GABA release from interneuron terminals.

• Brain areas involved in speech production.

  Authors: Nina Dronkers, Jennifer Ogar

  Brain : a journal of neurology. 127(Pt 7):1461-2.

• The impact of sex and language dominance on material-specific memory before and after left temporal lobe surgery.

  Authors: C Helmstaedter, T Brosch, M Kurthen, C E Elger

  Brain : a journal of neurology. 127(Pt 7):1518-25.

  Recent findings raised evidence that in early-onset left temporal lobe epilepsy, women show greater functional plasticity for verbal memory than men. In particular, women with lesion- orRecent findings raised evidence that in early-onset left temporal lobe epilepsy, women show greater functional plasticity for verbal memory than men. In particular, women with lesion- or epilepsy-driven atypical language dominance show an advantage over men. The question asked in this study was whether there is evidence of sex- and language dominance-dependent late, i.e. adult age, plasticity for verbal memory when epilepsy surgery is performed in these patients. Pre- and 1-year postoperative memory performance was evaluated in 169 patients (94 males and 75 females) who underwent left temporal lobe surgery and who had WADA testing of hemispheric language dominance prior to surgery. Verbal memory and figural memory were assessed by list-learning paradigms. According to the Bonn intracarotid amobarbital test (IAT) protocol, patients were categorized into left dominant or atypically dominant (right, incomplete left or right, and bilateral dominant) groups. Results were controlled for the hypothesized sex differences. Thirty-four percent of men and 47% of women displayed patterns of atypical language dominance. Atypical dominance was related to an early onset of epilepsy. Men showed a larger time window for development of atypical dominance but, differently from women, the pattern of atypical dominance was more strictly determined by the age at onset of epilepsy. Atypically dominant women showed better verbal memory than typically dominant women or men. After surgery, right dominant patients had better verbal memory outcome than patients with bilateral or left language dominance who showed significant memory loss. No effect of sex on verbal memory change was found. Figural memory deteriorated in men and improved in women, when they were not left dominant. Seizure outcome had no effect on performance changes. It was concluded that better preserved verbal memory in atypically dominant women before surgery indicates greater benefit from atypical dominance in women than men with regard to the initial damage associated with left hemisphere epilepsy. Later in life, when epilepsy surgery causes additional damage, no such sex difference is observed, indicating that the women's advantage over men is fixed to an early time window in life. Postoperative changes in figural memory suggest dynamics in crowding and suppression patterns. Whether this reflects late plasticity and compensation needs further demonstration. For clinical practice, it is important to note that incomplete right hemisphere and bilateral language dominance do not protect against verbal memory loss after left-sided temporal lobe surgery.

• Skin denervation in type 2 diabetes: correlations with diabetic duration and functional impairments.

  Authors: Chia-Tung Shun, Yang-Chyuan Chang, Huey-Peir Wu, Song-Chou Hsieh, Whei-Min Lin, Yea-Hui Lin, Tong-Yuan Tai, Sung-Tsang Hsieh

  Brain : a journal of neurology. 127(Pt 7):1593-605.

  Sensory neuropathy is a prominent component of diabetic neuropathy. It is not entirely clear how diabetes influences skin innervation, and whether these changes are correlated with clinical signs andSensory neuropathy is a prominent component of diabetic neuropathy. It is not entirely clear how diabetes influences skin innervation, and whether these changes are correlated with clinical signs and laboratory findings. To investigate these issues, we performed skin biopsies on the distal leg of 38 consecutive type 2 diabetic patients with sensory symptoms in lower limbs (25 males and 13 females, aged 56.2 +/- 9.4 years) and analysed the correlations of intraepidermal nerve fibre (IENF) densities in skin with glycaemic status (duration of diabetes, HbA1C, and fasting and post-prandial glucose levels), and functional parameters of small fibres (warm and cold thresholds) and large fibres (vibratory threshold and parameters of nerve conduction studies). Clinically, 23 patients (60.5%) had signs of small-fibre impairment, and 19 patients (50.0%) had signs of large-fibre impairment. IENF densities were much lower in diabetic patients than in age- and gender-matched controls (1.794 +/- 2.120 versus 9.359 +/- 3.466 fibres/mm, P < 0.0001), and 81.6% (31/38) of diabetic patients had reduced IENF densities. IENF densities were negatively associated with the duration of diabetes (standardized coefficient: -0.422, P = 0.015) by analysis with a multivariate linear regression model. Abnormal results of functional examinations were present in 81.6% (warm threshold), 57.9% (cold threshold), 63.2% (vibratory threshold) and 49% (amplitude of sural sensory action potential) of diabetic patients. Among the three sensory thresholds, the warm threshold temperature had the highest correlation with IENF densities (standardized coefficient: -0.773, P < 0.0001). On nerve conduction studies in lower-limb nerves, there were abnormal responses in 54.1% of sural nerves, and 50.0% of peroneal nerves. Of neurophysiological parameters, the amplitude of the sural sensory action potential had the highest correlation with IENF density (standardized coefficient: 0.739, P < 0.0001). On clinical examination, 15 patients showed no sign of small-fibre impairment, but seven of these patients had reduced IENF densities. In conclusion, small-fibre sensory neuropathy presenting with reduced IENF densities and correlated elevation of warm thresholds is a major manifestation of type 2 diabetes. In addition, the extent of skin denervation increases with diabetic duration.

• Electromyographic profiles of gait prior to onset of freezing episodes in patients with Parkinson's disease.

  Authors: Alice Nieuwboer, René Dom, Willy De Weerdt, Kaat Desloovere, Luc Janssens, Vangheluwe Stijn

  Brain : a journal of neurology. 127(Pt 7):1650-60.

  Freezing in Parkinson's disease is a severe and disabling problem of unknown aetiology. The aim of this study was to analyse the temporal pattern and the magnitude of the electromyographic activityFreezing in Parkinson's disease is a severe and disabling problem of unknown aetiology. The aim of this study was to analyse the temporal pattern and the magnitude of the electromyographic activity of the lower limb muscles just before freezing and to compare this with a voluntary stop and ongoing gait. We recruited 11 patients with a mean age of 64.8 years (SD 5.1) and a mean Unified Parkinson Disease Rating Scale (part III--off) score of 29 (SD 7.9). Within a standard 3D gait laboratory setting, surface electromyographic (EMG) data of the tibialis anterior (TA) and gastrocnemius (GS) muscles were collected using a portable EMG module. Patients in the off-phase of the medication cycle performed several trials of normal walking and voluntary stops or were exposed to freezing-provoking circumstances. Filtered EMG signals were rectified, smoothed and expressed as a percentage of the gait cycle. EMG onset was determined using a preset threshold, corrected after visual inspection. The magnitude of EMG was calculated by integrating EMG signals (iEMG) over (real) time. To control for the altered timing of activity, iEMG was also normalized for time (iEMGnormt). Analysis of variance of repeated measures analysis showed that significantly abnormal timing occurred in the TA and GS muscles with overall preserved reciprocity. Before freezing, TA swing activity already started prematurely during the pre-swing phase, whereas it was significantly shortened during the actual swing phase. For the GS muscle, a similar pattern of premature activation and termination was found during the stance phase before a freeze. GS activity also showed prolonged bursts of activity during the swing phase, not present during the normal and stop condition. Total iEMG activity of both TA and GS was significantly reduced during the pre-freezing gait cycles. However, when controlling for the altered duration of the bursts, the average iEMGnormt increased, as did the peak EMG in TA. In GS, iEMGnormt was not different in the three conditions. In conclusion, our data show that a consistent pattern of premature timing of TA and GS activity occurred before freezing, which was interpreted as a disturbance of central gait cycle timing. The total amount of EMG activity was reduced in both lower limb muscles due to the shortened time in which the muscles were active. In contrast to GS, activity in TA showed increased amplitudes of the EMG bursts, indicating a compensation strategy of pulling the leg into swing. The observed changes contribute to insufficient forward progression, deceleration and eventually a breakdown of movement.

• Posterior fossa lesion volume and slowed information processing in multiple sclerosis.

  Authors: Catherine J Archibald, Xingchang Wei, James N Scott, Carla J Wallace, Yunyan Zhang, Luanne M Metz, J Ross Mitchell

  Brain : a journal of neurology. 127(Pt 7):1526-34.

  The relationship between performance on information processing efficiency measures and MRI-derived lesion volume including global and regional T2 and T1 lesion volumes was investigated in 20 patientsThe relationship between performance on information processing efficiency measures and MRI-derived lesion volume including global and regional T2 and T1 lesion volumes was investigated in 20 patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). Processing speed, as measured by the Sternberg Memory Scanning Test, was significantly correlated with posterior fossa lesion volume and slowed reaction time in seven out of eight patients (six out of seven with SPMS) with any lesion volume in the posterior fossa suggesting a 'threshold effect'. Processing capacity as measured by the Salthouse Keeping Track Test was not significantly correlated with the MRI measures. Cognitive performance did not correlate with Expanded Disability Status Scale score, depression or fatigue, and patients performed within normal limits on tests of attention/concentration ability. The significant relationship between posterior fossa lesion volume and memory scanning speed in this study suggests that pathological damage in the posterior fossa may contribute to slowed cognitive processing and may be an important direction for future studies of cognitive function in multiple sclerosis. Lack of correlation of cognitive measures with the other MRI measures may be due to low lesion volume relative to other studies, sample composition, and limited pathological specificity of the MRI measures.

• Re-examining the brain regions crucial for orchestrating speech articulation.

  Authors: Argye E Hillis, Melissa Work, Peter B Barker, Michael A Jacobs, Elisabeth L Breese, Kristin Maurer

  Brain : a journal of neurology. 127(Pt 7):1479-87.

  A traditional method of localizing brain functions has been to identify shared areas of brain damage in individuals who have a particular deficit. The rationale of this 'lesion overlap' approach isA traditional method of localizing brain functions has been to identify shared areas of brain damage in individuals who have a particular deficit. The rationale of this 'lesion overlap' approach is straightforward: if the individuals can no longer perform the function, the area of brain damaged in most of these individuals must have been responsible for that function. However, the reciprocal association, i.e. the probability of the lesion causing the deficit, is often not evaluated. In this study, we illustrate potential weaknesses of this approach, by re-examining regions of the brain essential for orchestrating speech articulation. A particularly elegant and widely cited lesion overlap study identified the superior part of the precentral gyrus of the insula (in the anterior insula) as the shared area of damage in chronic stroke patients with 'apraxia of speech', a disorder of motor planning and programming of speech. Others have confirmed that patients with apraxia of speech commonly have damage to the anterior insula. However, this reliable association might reflect the vulnerability of the insula to damage following occlusion or narrowing of the middle cerebral artery (which can independently cause apraxia of speech and many other deficits). To evaluate this possibility, we examined the relationship between apraxia of speech and the insula in three unique ways: (i) we determined the probability of the lesion causing the deficit, as well as the deficit being associated with the lesion, by examining speech articulation and advanced MRIs in two consecutive series of patients with acute left hemisphere, non-lacunar stroke, 40 with and 40 without insular damage; (ii) we studied patients at stroke onset to identify the deficit before it resolved in cases of small stroke; and (iii) we identified regions of dysfunctional brain tissue, as well as structural damage. Using this approach, we found no association between apraxia of speech and lesions of the left insula, anterior insula or superior tip of the precentral gyrus of the insula. Instead, in patients with and without insular lesions, apraxia of speech was associated with structural damage or low blood flow in left posterior inferior frontal gyrus. These results illustrate a potential limitation of lesion overlap studies, and illustrate an alternative method for identifying brain-behaviour relationships.

• Does language lateralization depend on the hippocampus?

  Authors: Stefan Knecht

  Brain : a journal of neurology. 127(Pt 6):1217-8.

• The human basis pontis: motor syndromes and topographic organization.

  Authors: Jeremy D Schmahmann, Ryeowon Ko, Jason MacMore

  Brain : a journal of neurology. 127(Pt 6):1269-91.

  Clinical-anatomic correlations were performed in 25 patients with focal infarcts in the basilar pons to determine whether pontine lacunar syndromes conform to discrete clinical entities, and whetherClinical-anatomic correlations were performed in 25 patients with focal infarcts in the basilar pons to determine whether pontine lacunar syndromes conform to discrete clinical entities, and whether there is topographic organization of the motor system within the human basis pontis. Twelve clinical signs were scored on a 6-point scale, neuroimaging lesions were mapped and defined with statistical certainty, and structure-function correlation was performed to develop a topographic map of motor function. Clinical findings ranged from major devastation following extensive lesions (pure motor hemiplegia) to incomplete basilar pontine syndrome and restricted deficits after small focal lesions (ataxic hemiparesis, dysarthria-clumsy hand syndrome, dysarthria-dysmetria and dysarthria-facial paresis). The syndromes are not absolutely discrete, and are distinguished from each other by the relative degree of involvement of each clinical feature. Structure-function correlations indicate that strength is conveyed by the corticofugal fibres destined for the spinal cord, whereas dysmetria results from lesions involving the neurons of the basilar pons that link the ipsilateral cerebral cortex with the contralateral cerebellar hemisphere. Facial movement and articulation are localized to rostral and medial basilar pons; hand coordination is medial and ventral in rostral and mid-pons; and arm function is represented ventral and lateral to the hand. Leg coordination is in the caudal half of the pons, with lateral predominance. Swallowing is dependent upon the integrity of a number of regions in the rostral pons. Gait is in medial and lateral locations throughout the rostral- caudal extent of the pons. Dysmetria ipsilateral to the lesion constitutes a disconnection syndrome, as it occurs when the hemipontine lesion is extensive and interrupts pontocerebellar fibres traversing from the opposite, intact side of the pons. The heterogeneity of manifestations reflects the well-organized topography of motor function in the human basis pontis, in agreement with the anatomic organization of the motor corticopontine projections in the monkey. Higher order impairments including motor neglect, paraphasic errors and pathological laughter result from rostral and medial pontine lesions, and may result from disruption of the pontine component of associative corticopontocerebellar circuits.

• Pregnancy and multiple sclerosis (the PRIMS study): clinical predictors of post-partum relapse.

  Authors: Sandra Vukusic, Michael Hutchinson, Martine Hours, Thibault Moreau, Patricia Cortinovis-Tourniaire, Patrice Adeleine, Christian Confavreux, The Pregnancy In Multiple Sclerosis Group

  Brain : a journal of neurology. 127(Pt 6):1353-60.

  The influence of pregnancy in multiple sclerosis has been a matter of controversy for a long time. The Pregnancy in Multiple Sclerosis (PRIMS) study was the first large prospective study which aimedThe influence of pregnancy in multiple sclerosis has been a matter of controversy for a long time. The Pregnancy in Multiple Sclerosis (PRIMS) study was the first large prospective study which aimed to assess the possible influence of pregnancy and delivery on the clinical course of multiple sclerosis. We report here the 2-year post-partum follow-up and an analysis of clinical factors which might predict the likelihood of a relapse in the 3 months after delivery. The relapse rate in each trimester up to the end of the second year post-partum was compared with that in the pre-pregnancy year. Clinical predictors of the presence or absence of a post-partum relapse were analysed by logistic regression analysis. Using the best multivariate model, women were classified as having or not having a post-partum relapse predicted, and this was compared with the observed outcome. The results showed that, compared with the pre-pregnancy year, there was a reduction in the relapse rate during pregnancy, most marked in the third trimester, and a marked increase in the first 3 months after delivery. Thereafter, from the second trimester onwards and for the following 21 months, the annualized relapse rate fell slightly but did not differ significantly from the relapse rate recorded in the pre-pregnancy year. Despite the increased risk for the 3 months post-partum, 72% of the women did not experience any relapse during this period. Confirmed disability continued to progress steadily during the study period. Three indices, an increased relapse rate in the pre-pregnancy year, an increased relapse rate during pregnancy and a higher DSS (Kurtzke's Disability Status Scale) score at pregnancy onset, significantly correlated with the occurrence of a post-partum relapse. Neither epidural analgesia nor breast-feeding was predictive. When comparing the predicted and observed status, however, only 72% of the women were correctly classified by the multivariate model. In conclusion, the results for the second year post-partum confirm that the relapse rate remains similar to that of the pre-pregnancy year, after an increase in the first trimester following delivery. Women with greater disease activity in the year before pregnancy and during pregnancy have a higher risk of relapse in the post- partum 3 months. This is, however, not sufficient to identify in advance women with multiple sclerosis who are more likely to relapse, especially for planning therapeutic trials aiming to prevent post-partum relapses.

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