Brain - Advance Access

Shortened internodal length of dermal myelinated nerve fibres in Charcot-Marie-Tooth disease type 1A

Saporta, M. A., Katona, I., Lewis, R. A., Masse, S., Shy, M. E., Li, J. — Wed, 18 Nov 2009 05:42:45 PST

Charcot–Marie-Tooth disease type 1A is the most common inherited neuropathy and is caused by duplication of chromosome 17p11.2 containing the peripheral myelin protein-22 gene. This disease is characterized by uniform slowing of conduction velocities and secondary axonal loss, which are in contrast with non-uniform slowing of conduction velocities in acquired demyelinating disorders, such as chronic inflammatory demyelinating polyradiculoneuropathy. Mechanisms responsible for the slowed conduction velocities and axonal loss in Charcot–Marie-Tooth disease type 1A are poorly understood, in part because of the difficulty in obtaining nerve samples from patients, due to the invasive nature of nerve biopsies. We have utilized glabrous skin biopsies, a minimally invasive procedure, to evaluate these issues systematically in patients with Charcot–Marie-Tooth disease type 1A (n = 32), chronic inflammatory demyelinating polyradiculoneuropathy (n = 4) and healthy controls (n = 12). Morphology and molecular architecture of dermal myelinated nerve fibres were examined using immunohistochemistry and electron microscopy. Internodal length was uniformly shortened in patients with Charcot–Marie-Tooth disease type 1A, compared with those in normal controls (P < 0.0001). Segmental demyelination was absent in the Charcot–Marie-Tooth disease type 1A group, but identifiable in all patients with chronic inflammatory demyelinating polyradiculoneuropathy. Axonal loss was measurable using the density of Meissner corpuscles and associated with an accumulation of intra-axonal mitochondria. Our study demonstrates that skin biopsy can reveal pathological and molecular architectural changes that distinguish inherited from acquired demyelinating neuropathies. Uniformly shortened internodal length in Charcot–Marie-Tooth disease type 1A suggests a potential developmental defect of internodal lengthening. Intra-axonal accumulation of mitochondria provides new insights into the pathogenesis of axonal degeneration in Charcot–Marie-Tooth disease type 1A.

Neural correlates of psychotic symptoms in dementia with Lewy bodies

Nagahama, Y., Okina, T., Suzuki, N., Matsuda, M. — Tue, 17 Nov 2009 06:07:39 PST

The aim of this study was to investigate the association between psychotic symptoms in dementia with Lewy bodies and brain perfusion on single photon emission tomography. Based on factor analysis in 145 patients, psychotic symptoms were classified into five symptom domains (factor 1 to 4-related symptoms and delusions). The relationship between each symptom domain and brain perfusion was assessed in 100 patients with dementia with Lewy bodies, while accounting for the effects of age, sex, dementia severity, parkinsonism and dysphoria. Factor 1 symptoms (Capgras syndrome, phantom boarder, reduplication of person and place and misidentification of person) represented misidentifications, and were significantly related to hypoperfusion in the left hippocampus, insula, ventral striatum and bilateral inferior frontal gyri. Factor 3 symptoms (visual hallucination of person and feeling of presence) represented hallucinations of person and were related to hypoperfusion in the left ventral occipital gyrus and bilateral parietal areas. Delusions of theft and persecution were associated with relative hyperperfusion in the right rostral medial frontal cortex, left medial superior frontal gyrus and bilateral dorsolateral frontal cortices. This study revealed that different psychotic symptoms in dementia with Lewy bodies were associated with distinguishable cerebral networks. Visual hallucinations were related to dysfunction of the parietal and occipital association cortices, misidentifications were related to dysfunction of the limbic-paralimbic structures and delusions were related to dysfunction of the frontal cortices. Our findings provide important insights into the pathophysiological mechanisms underlying psychotic symptoms in dementia with Lewy bodies.

Mapping interictal oscillations greater than 200 Hz recorded with intracranial macroelectrodes in human epilepsy

Tue, 17 Nov 2009 06:07:37 PST

Interictal high-frequency oscillations over 200 Hz have been recorded with microelectrodes in the seizure onset zone of epileptic patients suffering from mesial temporal lobe epilepsy. Recent work suggests that similar high-frequency oscillations can be detected in the seizure onset zone using standard diagnostic macroelectrodes. However, only a few channels were examined in these studies, so little information is available on the spatial extent of high-frequency oscillations. Here, we present data on high-frequency oscillations recorded from a larger number of intracerebral contacts spatial (mean 38) in 16 patients. Data were obtained from 1 h of interictal recording sampled at 1024 Hz and was analysed using a new semi-automatic detection procedure based on a wavelet decomposition. A detailed frequency analysis permitted a rapid and reliable discrimination of high-frequency oscillations from other high-frequency events. A total of 1932 high-frequency oscillations were detected with an average frequency of 261 ± 53 Hz, amplitude of 11.9 ± 6.7 µV and duration of 22.7 ± 11.6 ms. Records from a patient often showed several different high-frequency oscillation patterns. We classified 24 patterns from 11 patients. Usually (20/24 patterns) high-frequency oscillations were nested in an epileptic paroxysm, such as a spike or a sharp wave, and typically high-frequency oscillations (19/24) were recorded from just one recording contact. Unexpectedly in other cases, high-frequency oscillations (5/24) were detected simultaneously on two or three contacts, sometimes separated by large distances. This large spatial extent suggests that high-frequency oscillations may sometimes result from a neuronal synchrony manifest on a scale of centimetres. High-frequency oscillations were almost always recorded in seizure-generating structures of patients suffering from mesial (9/9) or polar (1/3) temporal lobe epilepsy. They were never found in the epileptic or healthy basal, lateral temporal or extra temporal neocortex nor in the healthy amygdalo–hippocampal complex. These findings confirm that the generation of oscillations at frequencies higher that 200 Hz is, at this scale, a specific, intrinsic property of seizure-generating networks in medial and polar temporal lobes, which have a common archaic phylogenetic origin. We show that this activity can be detected and its spatial extent determined with conventional intracranial electroencephalography electrodes in records from patients with temporal lobe epilepsy. It is a reliable marker of the seizure onset zone that should be considered in decisions on surgical treatment.

Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis

Mon, 16 Nov 2009 07:21:42 PST

The non-dystrophic myotonias: molecular pathogenesis, diagnosis and treatment

Mon, 16 Nov 2009 07:21:40 PST

The non-dystrophic myotonias are an important group of skeletal muscle channelopathies electrophysiologically characterized by altered membrane excitability. Many distinct clinical phenotypes are now recognized and range in severity from severe neonatal myotonia with respiratory compromise through to milder late-onset myotonic muscle stiffness. Specific genetic mutations in the major skeletal muscle voltage gated chloride channel gene and in the voltage gated sodium channel gene are causative in most patients. Recent work has allowed more precise correlations between the genotype and the electrophysiological and clinical phenotype. The majority of patients with myotonia have either a primary or secondary loss of membrane chloride conductance predicted to result in reduction of the resting membrane potential. Causative mutations in the sodium channel gene result in an abnormal gain of sodium channel function that may show marked temperature dependence. Despite significant advances in the clinical, genetic and molecular pathophysiological understanding of these disorders, which we review here, there are important unresolved issues we address: (i) recent work suggests that specialized clinical neurophysiology can identify channel specific patterns and aid genetic diagnosis in many cases however, it is not yet clear if such techniques can be refined to predict the causative gene in all cases or even predict the precise genotype; (ii) although clinical experience indicates these patients can have significant progressive morbidity, the detailed natural history and determinants of morbidity have not been specifically studied in a prospective fashion; (iii) some patients develop myopathy, but its frequency, severity and possible response to treatment remains undetermined, furthermore, the pathophysiogical link between ion channel dysfunction and muscle degeneration is unknown; (iv) there is currently insufficient clinical trial evidence to recommend a standard treatment. Limited data suggest that sodium channel blocking agents have some efficacy. However, establishing the effectiveness of a therapy requires completion of multi-centre randomized controlled trials employing accurate outcome measures including reliable quantitation of myotonia. More specific pharmacological approaches are required and could include those which might preferentially reduce persistent muscle sodium currents or enhance the conductance of mutant chloride channels. Alternative strategies may be directed at preventing premature mutant channel degradation or correcting the mis-targeting of the mutant channels.

Absolute diffusivities define the landscape of white matter degeneration in Alzheimer's disease

Acosta-Cabronero, J., Williams, G. B., Pengas, G., Nestor, P. J. — Fri, 13 Nov 2009 02:54:40 PST

Recent imaging evidence in Alzheimer's disease suggests that neural involvement in early-stage disease is more complex than is encapsulated in the commonly held position of predominant mesial temporal lobe degeneration—there is also early posterior cingulate cortex and diencephalic damage. These findings suggest that early clinical Alzheimer's disease is underpinned by damage to an inter-connected network. If correct, this hypothesis would predict degeneration of the white matter pathways that connect this network. This prediction can be tested in vivo by diffusion magnetic resonance imaging. Most diffusion tensor imaging studies of white matter in neurodegenerative disorders such as Alzheimer's disease have concentrated on fractional anisotropy reductions and increased ‘apparent’ diffusivity; however, there is a lack of empirical biological evidence to assume that fractional anisotropy changes will necessarily capture the full extent of white matter changes in Alzheimer's disease. In this study, therefore, we undertook a comprehensive investigation of diffusion behaviour in Alzheimer's disease by analysing each of the component eigenvalues of the diffusion tensor in isolation to test the hypothesis that early Alzheimer's disease is associated with degeneration of a specific neural network. Using tract-based spatial statistics, we performed voxel-wise analyses of fractional anisotropy, axial, radial and mean diffusivities in 25 Alzheimer's disease patients compared with 13 elderly controls. We found that increased absolute (axial, radial and mean) diffusivities in Alzheimer's disease were concordant in a distribution consistent with the network hypothesis, highly statistically significant and far more sensitive than fractional anisotropy reductions. The former three measures identified confluent white matter abnormalities in parahippocampal gyrus and posterior cingulum, extending laterally into adjacent temporo-parietal regions as well as splenium and fornix. The caudal occipital lobe, temporal pole, genu and prefrontal white matter were relatively preserved. This distribution is highly consistent with expected predictions of tract degeneration from grey matter lesions identified by fluorodeoxyglucose positron emission tomography and structural magnetic resonance imaging. Concordant with results from these other imaging modalities, this pattern predominantly involves degeneration of the tracts connecting the circuit of Papez. These findings also highlight that early neuropathological processes are associated with changes of the diffusion ellipsoid that are predominantly proportional along all semi-principal axes.

Effects of baclofen on motor units paralysed by chronic cervical spinal cord injury

Thomas, C. K., Hager-Ross, C. K., Klein, C. S. — Tue, 10 Nov 2009 05:25:19 PST

Baclofen, a gamma-aminobutyric acid receptor_B agonist, is used to reduce symptoms of spasticity (hyperreflexia, increases in muscle tone, involuntary muscle activity), but the long-term effects of sustained baclofen use on skeletal muscle properties are unclear. The aim of our study was to evaluate whether baclofen use and paralysis due to cervical spinal cord injury change the contractile properties of human thenar motor units more than paralysis alone. Evoked electromyographic activity and force were recorded in response to intraneural stimulation of single motor axons to thenar motor units. Data from three groups of motor units were compared: 23 paralysed units from spinal cord injured subjects who take baclofen and have done so for a median of 7 years, 25 paralysed units from spinal cord injured subjects who do not take baclofen (median: 10 years) and 45 units from uninjured control subjects. Paralysed motor unit properties were independent of injury duration and level. With paralysis and baclofen, the median motor unit tetanic forces were significantly weaker, twitch half-relaxation times longer and half maximal forces reached at lower frequencies than for units from uninjured subjects. The median values for these same parameters after paralysis alone were comparable to control data. Axon conduction velocities differed across groups and were slowest for paralysed units from subjects who were not taking baclofen and fastest for units from the uninjured. Greater motor unit weakness with long-term baclofen use and paralysis will make the whole muscle weaker and more fatigable. Significantly more paralysed motor units need to be excited during patterned electrical stimulation to produce any given force over time. The short-term benefits of baclofen on spasticity (e.g. management of muscle spasms that may otherwise hinder movement or social interactions) therefore have to be considered in relation to its possible long-term effects on muscle rehabilitation. Restoring the strength and speed of paralysed muscles to pre-injury levels may require more extensive therapy when baclofen is used chronically.

Brain {alpha}-synuclein accumulation in multiple system atrophy, Parkinson's disease and progressive supranuclear palsy: a comparative investigation

Tue, 10 Nov 2009 05:25:18 PST

-Synuclein is a major component of Lewy bodies and glial cytoplasmic inclusions, pathological hallmarks of idiopathic Parkinson's disease and multiple system atrophy, and it is assumed to be aetiologically involved in these conditions. However, the quantitative status of brain -synuclein in different Parkinsonian disorders is still unresolved and it is uncertain whether -synuclein accumulation is restricted to regions of pathology. We compared membrane-associated, sodium dodecyl sulfate-soluble -synuclein, both the full-length 17 kDa and high molecular weight species, by western blotting in autopsied brain of patients with Parkinson's disease (brainstem-predominant Lewy body disease: n = 9), multiple system atrophy (n = 11), progressive supranuclear palsy (n = 16), and of normal controls (n = 13). Brain of a patient with familial Parkinsonism-dementia due to -synuclein locus triplication (as positive control) showed increased membrane-associated, sodium dodecyl sulfate-soluble -synuclein levels with abundant high molecular weight immunoreactivity. In multiple system atrophy, a massive increase in 17 kDa membrane-associated, sodium dodecyl sulfate-soluble -synuclein was observed in highly pathologically affected regions, including putamen (+1760%, range +625–2900%), substantia nigra [+1000% (+356–1850%)], and white matter of internal capsule [+2210% (+430–6830%)] together with numerous high molecular weight species. Levels of 17 kDa membrane-associated, sodium dodecyl sulfate-soluble -synuclein were only modestly increased in less affected areas (cerebellar cortex, +95%; caudate, +30%; with both also showing numerous high molecular weight species) and were generally normal in cerebral cortices. In both Parkinson's disease and progressive supranuclear palsy, membrane-associated, sodium dodecyl sulfate-soluble -synuclein levels were normal in putamen and frontal cortex whereas a trend was observed for variably increased 17 kDa membrane-associated, sodium dodecyl sulfate-soluble -synuclein concentrations [+184% (–60% to +618%)] with additional high molecular weight species in Parkinson's disease substantia nigra. No obvious correlation was observed between nigral membrane-associated, sodium dodecyl sulfate-soluble -synuclein accumulation and Lewy body density in Parkinson's disease. Two progressive supranuclear palsy cases had membrane-associated, sodium dodecyl sulfate-soluble -synuclein accumulation in substantia nigra similar to multiple system atrophy. Several Parkinson's disease patients had very modest high molecular weight membrane-associated, sodium dodecyl sulfate-soluble -synuclein accumulation in putamen. Levels of 17-kDa membrane-associated, sodium dodecyl sulfate-soluble -synuclein were generally positively correlated with those of high molecular weight membrane-associated, sodium dodecyl sulfate-soluble -synuclein and there was a trend for a positive correlation between striatal dopamine loss and 17-kDa membrane-associated, sodium dodecyl sulfate-soluble -synuclein concentrations in multiple system atrophy. Brain membrane-associated, sodium dodecyl sulfate-soluble -synuclein accumulations in Parkinson's disease and multiple system atrophy are regionally specific, suggesting that these sporadic -synucleinopathies, unlike familial Parkinsonism-dementia, are not associated with a simple global over-expression of the protein. Despite a similar extent of dopamine depletion, the magnitude of brain membrane-associated, sodium dodecyl sulfate-soluble -synuclein changes is disease specific, with multiple system atrophy clearly having the most severe accumulation. Literature discrepancies on -synuclein status in ‘Parkinson's disease’ might be explained by inclusion of cases not having classic brainstem-predominant Lewy body disease and by variable -synuclein accumulation within this diagnostic classification.

The enigma of Gerstmann's syndrome revisited: a telling tale of the vicissitudes of neuropsychology

Rusconi, E., Pinel, P., Dehaene, S., Kleinschmidt, A. — Tue, 10 Nov 2009 05:25:16 PST

Eighty years ago, the Austrian neurologist Josef Gerstmann observed in a few patients a concomitant impairment in discriminating their own fingers, writing by hand, distinguishing left from right and performing calculations. He claimed that this tetrad of symptoms constituted a syndromal entity, assigned it to a lesion of the dominant parietal lobe and suggested that it was due to damage of a common functional denominator. Ever since, these claims have been debated and an astute synopsis and sceptical discussion was presented 40 years ago by MacDonald Critchley in this journal. Nonetheless, Gerstmann's syndrome has continued to intrigue both clinical neurologists and researchers in neuropsychology, and more frequently than not is described in textbooks as an example of parietal lobe damage. In this review, we revisit the chequered history of this syndrome, which can be seen as a case study of the dialectic evolution of concepts in neuropsychology. In light of several modern era findings of pure cases we conclude that it is legitimate to label the conjunction of symptoms first described by Gerstmann as a ‘syndrome’, but that it is very unlikely that damage to the same population of cortical neurons should account for all of the four symptoms. Instead, we propose that a pure form of Gerstmann's syndrome might arise from disconnection, via a lesion, to separate but co-localized fibre tracts in the subcortical parietal white matter, a hypothesis for which we have recently provided evidence using combined imaging of functional and structural organization in the healthy brain.

Anterior temporal lobe connectivity correlates with functional outcome after aphasic stroke

Warren, J. E., Crinion, J. T., Lambon Ralph, M. A., Wise, R. J. S. — Tue, 10 Nov 2009 05:25:16 PST

Focal brain lesions are assumed to produce language deficits by two basic mechanisms: local cortical dysfunction at the lesion site, and remote cortical dysfunction due to disruption of the transfer and integration of information between connected brain regions. However, functional imaging studies investigating language outcome after aphasic stroke have tended to focus only on the role of local cortical function. In this positron emission tomography functional imaging study, we explored relationships between language comprehension performance after aphasic stroke and the functional connectivity of a key speech-processing region in left anterolateral superior temporal cortex anterolateral superior temporal cortex. We compared the organization of left anterolateral superior temporal cortex functional connections during narrative speech comprehension in normal subjects with left anterolateral superior temporal cortex connectivity in a group of chronic aphasic stroke patients. We then evaluated the language deficits associated with altered left anterolateral superior temporal cortex connectivity in aphasic stroke. During normal narrative speech comprehension, left anterolateral superior temporal cortex displayed positive functional connections with left anterior basal temporal cortex, left inferior frontal gyrus and homotopic cortex in right anterolateral superior temporal cortex. As a group, aphasic patients demonstrated a selective disruption of the normal functional connection between left and right anterolateral superior temporal cortices. We observed that deficits in auditory single word and sentence comprehension correlated both with the degree of disruption of left-right anterolateral superior temporal cortical connectivity and with local activation in the anterolateral superior temporal cortex. Subgroup analysis revealed that aphasic patients with preserved positive intertemporal connectivity displayed better receptive language function; these patients also showed greater than normal left inferior frontal gyrus activity, suggesting a possible ‘top-down’ compensatory mechanism. These results demonstrate that functional connectivity between anterolateral superior temporal cortex and right anterior superior temporal cortex is a marker of receptive language outcome after aphasic stroke, and illustrate that language system organization after focal brain lesions may be marked by complex signatures of altered local and pathway-level function.

Executive function and fluid intelligence after frontal lobe lesions

Tue, 10 Nov 2009 05:25:14 PST

Many tests of specific ‘executive functions’ show deficits after frontal lobe lesions. These deficits appear on a background of reduced fluid intelligence, best measured with tests of novel problem solving. For a range of specific executive tests, we ask how far frontal deficits can be explained by a general fluid intelligence loss. For some widely used tests, e.g. Wisconsin Card Sorting, we find that fluid intelligence entirely explains frontal deficits. When patients and controls are matched on fluid intelligence, no further frontal deficit remains. For these tasks too, deficits are unrelated to lesion location within the frontal lobe. A second group of tasks, including tests of both cognitive (e.g. Hotel, Proverbs) and social (Faux Pas) function, shows a different pattern. Deficits are not fully explained by fluid intelligence and the data suggest association with lesions in the right anterior frontal cortex. Understanding of frontal lobe deficits may be clarified by separating reduced fluid intelligence, important in most or all tasks, from other more specific impairments and their associated regions of damage.

Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis

Tue, 10 Nov 2009 05:25:13 PST

Amyotrophic lateral sclerosis is a rapidly progressing fatal neurodegenerative disease characterized by the presence of protein inclusions within affected motor neurons. Endoplasmic reticulum stress leading to apoptosis was recently recognized to be an important process in the pathogenesis of sporadic human amyotrophic lateral sclerosis as well as in transgenic models of mutant superoxide dismutase 1-linked familial amyotrophic lateral sclerosis. Endoplasmic reticulum stress occurs early in disease, indicating a critical role in pathogenesis, and involves upregulation of an important endoplasmic reticulum chaperone, protein disulphide isomerase. We aimed to investigate the involvement of protein disulphide isomerase in endoplasmic reticulum stress induction, protein aggregation, inclusion formation and toxicity in amyotrophic lateral sclerosis. Motor neuron-like NSC-34 cell lines were transfected with superoxide dismutase 1 and protein disulphide isomerase encoding vectors and small interfering RNA, and examined by immunocytochemistry and immunoblotting. Expression of mutant superoxide dismutase 1 induced endoplasmic reticulum stress, predominantly in cells bearing mutant superoxide dismutase 1 inclusions but also in a proportion of cells expressing mutant superoxide dismutase 1 without visible inclusions. Over-expression of protein disulphide isomerase decreased mutant superoxide dismutase 1 aggregation, inclusion formation, endoplasmic reticulum stress induction and toxicity, whereas small interfering RNA targeting protein disulphide isomerase increased mutant superoxide dismutase 1 inclusion formation, indicating a protective role for protein disulphide isomerase against superoxide dismutase 1 misfolding. Aberrant modification of protein disulphide isomerase by S-nitrosylation of active site cysteine residues has previously been shown as an important process in neurodegeneration in Parkinson's and Alzheimer's disease brain tissue, but has not been described in amyotrophic lateral sclerosis. Using a biotin switch assay, we detected increased levels of S-nitrosylated protein disulphide isomerase in transgenic mutant superoxide dismutase 1 mouse and human sporadic amyotrophic lateral sclerosis spinal cord tissues. Hence, despite upregulation, protein disulphide isomerase is also functionally inactivated in amyotrophic lateral sclerosis, which may prevent its normal protective function and contribute to disease. We also found that a small molecule mimic of the protein disulphide isomerase active site, (±)-trans-1,2-bis(mercaptoacetamido)cyclohexane, protected against mutant superoxide dismutase 1 inclusion formation. These studies reveal that endoplasmic reticulum stress is important in the formation of mutant superoxide dismutase 1 inclusions, and protein disulphide isomerase has an important function in ameliorating mutant superoxide dismutase 1 aggregation and toxicity. Functional inhibition of protein disulphide isomerase by S-nitrosylation may contribute to pathophysiology in both mutant superoxide dismutase 1-linked disease and sporadic amyotrophic lateral sclerosis. Protein disulphide isomerase is therefore a novel potential therapeutic target in amyotrophic lateral sclerosis and (±)-trans-1,2-bis(mercaptoacetamido)cyclohexane and other molecular mimics of protein disulphide isomerase could be of benefit in amyotrophic lateral sclerosis and other neurodegenerative diseases related to protein misfolding.

Stereology of cerebral cortex after traumatic brain injury matched to the Glasgow Outcome Score

Maxwell, W. L., MacKinnon, M.-A., Stewart, J. E., Graham, D. I. — Fri, 06 Nov 2009 05:31:26 PST

Magnetic resonance imaging provides evidence for loss of both white and grey matter, in terms of tissue volume, from the cerebral hemispheres after traumatic brain injury. However, quantitative histopathological data are lacking. From the archive of the Department of Neuropathology at Glasgow, the cerebral cortex of 48 patients was investigated using stereology. Patients had survived 3 months after traumatic brain injury and were classified using the Glasgow Outcome Scale as follows: moderately disabled (n = 13), severely disabled (n = 12) and vegetative state (n = 12); and controls. Some patients from the archive were diagnosed with diffuse axonal injury post-mortem. Comparisons of changes in cortical neuron population across Glasgow Outcome Scale groups between diffuse axonal injury and non-diffuse axonal injury patients were undertaken using effect size analyses. The hypotheses tested were that (i) thinning of the cerebral cortex occurred after traumatic brain injury; (ii) changes in thickness of cortical layers in Brodmann areas 11, 10, 24a and 4 differed; and (iii) different changes occurred for neuronal number, their size and nearest neighbour index across Glasgow Outcome Scale groups. There was a greater loss of large pyramidal and large non-pyramidal neurons with a more severe score on the Glasgow Outcome Scale from all four cortical regions, with the greatest loss of neurons from the prefrontal cortex of patients with diffuse axonal injury. There were differences in the changes of number of medium and small pyramidal and non-pyramidal neurons between different cortical regions, and between patients with and without diffuse axonal injury. Generally, a decrease in the somatic diameter of pyramidal and non-pyramidal neurons was associated with a more severe clinical outcome. However, in the motor cortex a more severe Glasgow Outcome Scale was associated with an increased diameter of medium pyramidal neurons and small non-pyramidal cells. Pyramidal and non-pyramidal neurons did not follow a Poisson distribution within the neuropil of control patients. Pyramidal neurons were usually scattered while medium and small non-pyramidal neurons were clustered. An increased spacing between remaining neurons usually occurred across Glasgow Outcome Scale groups. It is concluded that loss of neurons resulted in reduced executive and integrative capability in patients after traumatic head injury.

The most important of all the organs: Darwin on the brain

Jacyna, S. — Thu, 05 Nov 2009 07:13:12 PST

This article discusses Charles Darwin's interest in topics that may broadly be defined as ‘neurological’ in character. Using published and manuscript materials, it examines the sources of Darwin's knowledge of neurological matters and seeks to explain why questions concerning the relation of mind and brain both in humans and other animals were relevant to his wider concerns. The paper concludes with a discussion of Darwin's impact on late 19th and early 20th century neurological thought. The 150th anniversary of the publication of the Origin of Species and the 200th of the birth of its author afford an opportunity to reflect on Charles Darwin's relationship to neurology. The first section of this article considers the part played by what might broadly be defined as ‘neurological’ materials in the shaping of Darwin's theory. The following section provides a brief review of the impact that Darwin's ideas were to have upon subsequent neurological thought.

Imaging studies in congenital anophthalmia reveal preservation of brain architecture in 'visual' cortex

Bridge, H., Cowey, A., Ragge, N., Watkins, K. — Thu, 05 Nov 2009 07:13:11 PST

The functional specialization of the human brain means that many regions are dedicated to processing a single sensory modality. When a modality is absent, as in congenital total blindness, ‘visual’ regions can be reliably activated by non-visual stimuli. The connections underlying this functional adaptation, however, remain elusive. In this study, using structural and diffusion-weighted magnetic resonance imaging, we investigated the structural differences in the brains of six bilaterally anophthalmic subjects compared with sighted subjects. Surprisingly, the gross structural differences in the brains were small, even in the occipital lobe where only a small region of the primary visual cortex showed a bilateral reduction in grey matter volume in the anophthalmic subjects compared with controls. Regions of increased cortical thickness were apparent on the banks of the Calcarine sulcus, but not in the fundus. Subcortically, the white matter volume around the optic tract and internal capsule in anophthalmic subjects showed a large decrease, yet the optic radiation volume did not differ significantly. However, the white matter integrity, as measured with fractional anisotropy showed an extensive reduction throughout the brain in the anophthalmic subjects, with the greatest difference in the optic radiations. In apparent contradiction to the latter finding, the connectivity between the lateral geniculate nucleus and primary visual cortex measured with diffusion tractography did not differ between the two populations. However, these findings can be reconciled by a demonstration that at least some of the reduction in fractional anisotropy in the optic radiation is due to an increase in the strength of fibres crossing the radiations. In summary, the major changes in the ‘visual’ brain in anophthalmic subjects may be subcortical, although the evidence of decreased fractional anisotropy and increased crossing fibres could indicate considerable re-organization.

Magnetic resonance imaging characteristics of children and adults with paediatric-onset multiple sclerosis

Thu, 05 Nov 2009 07:13:10 PST

The purpose of this study was to compare the clinical and quantitative magnetic resonance imaging metrics of paediatric-onset multiple sclerosis to adult-onset multiple sclerosis. It was a prospective comparison of clinical and magnetic resonance imaging characteristics of two paediatric onset multiple sclerosis and two adult onset multiple sclerosis groups that were matched for disease duration. The paediatric-onset-C group consisted of children with paediatric-onset multiple sclerosis with mean disease duration of 2.7 years, whereas the paediatric onset-A group consisted of adults with mean disease duration of 20 years. The adult onset multiple sclerosis-1 and adult onset multiple sclerosis-2 groups were matched to the paediatric onset-C and paediatric onset-A groups. The brain magnetic resonance imaging measures included: T₁-, T₂- and gadolinium contrast-enhancing volumes and the T₂-lesion volume relative magnetization transfer ratio, global and tissue specific white and grey matter brain atrophy and normal appearing grey and white matter magnetization transfer ratio. Regression analyses were employed for magnetic resonance imaging measures. The paediatric onset multiple sclerosis-C (n = 17) and adult onset multiple sclerosis-1 (n = 81) groups had mean disease duration values of 2.7 ± standard deviation 2.0 and 2.6 ± 1.1 years, respectively. The paediatric onset multiple sclerosis-A group (n = 33) and adult onset multiple sclerosis-2 group (n = 300) had mean disease durations of 20 ± standard deviation 10.9 and 20 ± 9.3 years, respectively. In regression analysis, the T₂- lesion volume of the paediatric onset multiple sclerosis-C and adult onset multiple sclerosis-1 groups were similar but there was a trend toward higher T₁- lesion volume (P = 0.028) in the paediatric onset group. The brain parenchymal fraction and grey matter fraction in the paediatric-onset multiple sclerosis-C group were higher than those for the adult onset multiple sclerosis-1 group (both P < 0.001). The frequency of progressive multiple sclerosis in the paediatric onset multiple sclerosis-A group (27.3%) trended lower (odds ratio = 0.43, P = 0.042) than that in the adult onset multiple sclerosis-2 group (46.3%). The Expanded Disability Status Scale (median; inter-quartile range) in the paediatric onset multiple sclerosis-A group (2.25; 2.5) trended lower (P = 0.058) compared with the adult onset multiple sclerosis-2 group (3.5; 4.0). There was a trend toward lower magnetization transfer ratio values in T₂-lesions, normal appearing grey matter and normal appearing white matter and higher grey matter fraction in the paediatric onset multiple sclerosis-A group compared with the adult onset multiple sclerosis-2 group. There was no evidence for differences on T₂-lesion volume, T₁-lesion volume, brain parenchymal fraction or white matter fraction. Paediatric-onset multiple sclerosis is characterized by a significant disease burden both early and later in the disease course. Despite this, disability is slower to accrue in paediatric onset multiple sclerosis than adult onset multiple sclerosis.

Reply to: Comment on alemtuzumab and inclusion body myositis

Thu, 05 Nov 2009 07:13:09 PST

Comment on alemtuzumab and inclusion body myositis

Greenberg, S. A. — Thu, 05 Nov 2009 07:13:09 PST

The left superior temporal gyrus is a shared substrate for auditory short-term memory and speech comprehension: evidence from 210 patients with stroke

Thu, 05 Nov 2009 07:13:08 PST

Competing theories of short-term memory function make specific predictions about the functional anatomy of auditory short-term memory and its role in language comprehension. We analysed high-resolution structural magnetic resonance images from 210 stroke patients and employed a novel voxel based analysis to test the relationship between auditory short-term memory and speech comprehension. Using digit span as an index of auditory short-term memory capacity we found that the structural integrity of a posterior region of the superior temporal gyrus and sulcus predicted auditory short-term memory capacity, even when performance on a range of other measures was factored out. We show that the integrity of this region also predicts the ability to comprehend spoken sentences. Our results therefore support cognitive models that posit a shared substrate between auditory short-term memory capacity and speech comprehension ability. The method applied here will be particularly useful for modelling structure–function relationships within other complex cognitive domains.

The natural history of Charcot-Marie-Tooth type 1A in adults: a 5-year follow-up study

Thu, 05 Nov 2009 04:08:48 PST

Charcot–Marie-Tooth type 1A is the most prevalent hereditary demyelinating polyneuropathy. The aim of this study was to investigate the natural history of the disease in adults during a 5-year follow-up and to compare the changes over time with those found in normal ageing. In a cohort of 46 adult Charcot–Marie-Tooth type 1A patients, impairments and physical disability were scored at baseline and at 1, 3 and 5 years. Standardized nerve conduction studies and electromyography were performed at baseline and at 5 years. Twenty-six healthy age- and sex-matched controls were evaluated at baseline and at 5 years. Forty-four of 46 Charcot–Marie-Tooth type 1A patients (range 17–69 years) and 26 controls (range 25–65 years) completed the 5-year follow-up. The decrease in muscle strength and in compound muscle action potential amplitudes was similar for patients and controls alike. However, in contrast to the control group, physical disability increased over time in the patient group. In patients, muscle strength and physical disability after 5 years were closely related to these parameters at baseline. None of the other assessed baseline characteristics, i.e. age, gender, compound muscle action potential amplitude and motor nerve conduction velocity, predicted the extent of deterioration of muscle strength or physical disability. In adult Charcot–Marie-Tooth type 1A patients, the decline in axonal function and in muscle strength may reflect, to a considerable extent, a process of normal ageing. The slow increase in physical disability in adulthood may well be explained by decreased reserves and compensatory mechanisms together with progression of skeletal deformations due to muscle weakness.

Mild cognitive impairment associated with limbic and neocortical lewy body disease: a clinicopathological study

Wed, 04 Nov 2009 03:56:44 PST

There are little data on the relationship between Lewy body disease and mild cognitive impairment syndromes. The Mayo Clinic aging and dementia databases in Rochester, Minnesota, and Jacksonville, Florida were queried for cases who were diagnosed with mild cognitive impairment between 1 January 1996 and 30 April 2008, were prospectively followed and were subsequently found to have autopsy-proven Lewy body disease. The presence of rapid eye movement sleep behaviour disorder was specifically assessed. Mild cognitive impairment subtypes were determined by clinical impression and neuropsychological profiles, based on prospective operational criteria. The diagnosis of clinically probable dementia with Lewy bodies was based on the 2005 McKeith criteria. Hippocampal volumes, rate of hippocampal atrophy, and proton magnetic resonance spectroscopy were assessed on available magnetic resonance imaging and spectroscopy scans. Eight subjects were identified; six were male. Seven developed dementia with Lewy bodies prior to death; one died characterized as mild cognitive impairment. The number of cases and median age of onset (range) for specific features were: seven with rapid eye movement sleep behaviour disorder—60 years (27–91 years), eight with cognitive symptoms—69 years (62–89 years), eight with mild cognitive impairment—70.5 years (66–91 years), eight with parkinsonism symptoms—71 years (66–92 years), six with visual hallucinations—72 years (64–90 years), seven with dementia—75 years (67–92 years), six with fluctuations in cognition and/or arousal—76 years (68–92 years) and eight dead—76 years (71–94 years). Rapid eye movement sleep behaviour disorder preceded cognitive symptom onset in six cases by a median of 10 years (2–47 years) and mild cognitive impairment diagnosis by a median of 12 years (3–48 years). The mild cognitive impairment subtypes represented include: two with single domain non-amnestic mild cognitive impairment, three with multi-domain non-amnestic mild cognitive impairment, and three with multi-domain amnestic mild cognitive impairment. The cognitive domains most frequently affected were attention and executive functioning, and visuospatial functioning. Hippocampal volumes and the rate of hippocampal atrophy were, on average, within the normal range in the three cases who underwent magnetic resonance imaging, and the choline/creatine ratio was elevated in the two cases who underwent proton magnetic resonance spectroscopy when they were diagnosed as mild cognitive impairment. On autopsy, six had neocortical-predominant Lewy body disease and two had limbic-predominant Lewy body disease; only one had coexisting high-likelihood Alzheimer's disease. These findings indicate that among Lewy body disease cases that pass through a mild cognitive impairment stage, any cognitive pattern or mild cognitive subtype is possible, with the attention/executive and visuospatial domains most frequently impaired. Hippocampal volume and proton magnetic resonance spectroscopy data were consistent with recent data in dementia with Lewy bodies. All cases with rapid eye movement sleep behaviour disorder and mild cognitive impairment were eventually shown to have autopsy-proven Lewy body disease, indicating that rapid eye movement sleep behaviour disorder plus mild cognitive impairment probably reflects brainstem and cerebral Lewy body disease.

The psychophysics of visual motion and global form processing in autism

Koldewyn, K., Whitney, D., Rivera, S. M. — Tue, 03 Nov 2009 04:20:37 PST

Several groups have recently reported that people with autism may suffer from a deficit in visual motion processing and proposed that these deficits may be related to a general dorsal stream dysfunction. In order to test the dorsal stream deficit hypothesis, we investigated coherent and biological motion perception as well as coherent form perception in a group of adolescents with autism and a group of age-matched typically developing controls. If the dorsal stream hypothesis were true, we would expect to document deficits in both coherent and biological motion processing in this group but find no deficit in coherent form perception. Using the method of constant stimuli and standard psychophysical analysis techniques, we measured thresholds for coherent motion, biological motion and coherent form. We found that adolescents with autism showed reduced sensitivity to both coherent and biological motion but performed as well as age-matched controls during coherent form perception. Correlations between intelligence quotient and task performance, however, appear to drive much of the group difference in coherent motion perception. Differences between groups on coherent motion perception did not remain significant when intelligence quotient was controlled for, but group differences in biological motion perception were more robust, remaining significant even when intelligence quotient differences were accounted for. Additionally, aspects of task performance on the biological motion perception task were related to autism symptomatology. These results do not support a general dorsal stream dysfunction in adolescents with autism but provide evidence of a more complex impairment in higher-level dynamic attentional processes.

Voxel-based morphometry reveals reduced grey matter volume in the temporal cortex of developmental prosopagnosics

Tue, 03 Nov 2009 04:20:36 PST

Individuals with developmental prosopagnosia exhibit severe and lasting difficulties in recognizing faces despite the absence of apparent brain abnormalities. We used voxel-based morphometry to investigate whether developmental prosopagnosics show subtle neuroanatomical differences from controls. An analysis based on segmentation of T1-weighted images from 17 developmental prosopagnosics and 18 matched controls revealed that they had reduced grey matter volume in the right anterior inferior temporal lobe and in the superior temporal sulcus/middle temporal gyrus bilaterally. In addition, a voxel-based morphometry analysis based on the segmentation of magnetization transfer parameter maps showed that developmental prosopagnosics also had reduced grey matter volume in the right middle fusiform gyrus and the inferior temporal gyrus. Multiple regression analyses relating three distinct behavioural component scores, derived from a principal component analysis, to grey matter volume revealed an association between a component related to facial identity and grey matter volume in the left superior temporal sulcus/middle temporal gyrus plus the right middle fusiform gyrus/inferior temporal gyrus. Grey matter volume in the lateral occipital cortex was associated with component scores related to object recognition tasks. Our results demonstrate that developmental prosopagnosics have reduced grey matter volume in several regions known to respond selectively to faces and provide new evidence that integrity of these areas relates to face recognition ability.

Cellular structure of the human cerebral cortex

Jones, E. G. — Tue, 27 Oct 2009 09:27:27 PDT

The ratio of 'deleted in colorectal cancer' to 'uncoordinated-5A' netrin-1 receptors on the growth cone regulates mossy fibre directionality

Muramatsu, R., Nakahara, S., Ichikawa, J., Watanabe, K., Matsuki, N., Koyama, R. — Sun, 25 Oct 2009 20:59:26 PDT

Proper axonal targeting is fundamental to the establishment of functional neural circuits. The hippocampal mossy fibres normally project towards the CA3 region. In the hippocampi of patients with temporal lobe epilepsy and related animal models, however, mossy fibres project towards the molecular layer and produce the hyperexcitable recurrent networks. The cellular and molecular mechanisms underlying this aberrant axonal targeting, known as mossy fibre sprouting, remain unclear. Netrin-1 attracts or repels axons depending on the composition of its attraction-mediating receptor, deleted in colorectal cancer, and its repulsion-mediating receptor, uncoordinated-5, on the growth cone; but the roles of netrin-1-dependent guidance in pathological conditions are largely unknown. In this study, we examined the role of netrin-1 and its receptors in mossy fibre guidance and report that enhanced neuronal activity changes netrin-1-mediated cell targeting by the axons under hyperexcitable conditions. Netrin-1 antibody or Dcc ribonucleic acid interference attenuated mossy fibre growth towards CA3 in slice overlay assays. The axons were repelled from CA3 and ultimately innervated the molecular layer when hyperactivity was pharmacologically introduced. We first hypothesized that a reduction in netrin-1 expression in CA3 underlies the phenomenon, but found that its expression was increased. We then examined two possible activity-dependent changes in netrin-1 receptor expression: a reduction in the deleted in colorectal cancer receptor and induction of uncoordinated-5 receptor. Hyperactivity did not affect the surface expression of the deleted in colorectal cancer receptor on the growth cone, but it increased that of uncoordinated-5A, which was suppressed by blocking cyclic adenosine monophosphate signalling. In addition, Dcc knockdown did not affect hyperactivity-induced mossy fibre sprouting in the slice cultures, whereas Unc5a knockdown rescued the mistargeting. Thus, netrin-1 appears to attract mossy fibres via the deleted in colorectal cancer receptor, while it repels them via cyclic adenosine monophosphate-induced uncoordinated-5A under hyperexcitable conditions, resulting in mossy fibre sprouting.

Cerebrospinal hypocretin, daytime sleepiness and sleep architecture in Parkinson's disease dementia

Sun, 25 Oct 2009 20:59:25 PDT

Excessive daytime sleepiness is common in Parkinson's disease and has been associated with Parkinson's disease-related dementia. Narcoleptic features have been observed in Parkinson's disease patients with excessive daytime sleepiness and hypocretin cell loss has been found in the hypothalamus of Parkinson's disease patients, in association with advanced disease. However, studies on cerebrospinal fluid levels of hypocretin-1 (orexin A) in Parkinson's disease have been inconclusive. Reports of sleep studies in Parkinson's disease patients with and without excessive daytime sleepiness have also been disparate, pointing towards a variety of causes underlying excessive daytime sleepiness. In this study, we aimed to measure cerebrospinal fluid hypocretin-1 levels in Parkinson's disease patients with and without dementia and to study their relationship to dementia and clinical excessive daytime sleepiness, as well as to describe potentially related sleep architecture changes. Twenty-one Parkinson's disease patients without dementia and 20 Parkinson's disease patients with dementia, along with 22 control subjects without sleep complaints, were included. Both Epworth sleepiness scale, obtained with the help of the caregivers, and mini-mental state examination were recorded. Lumbar cerebrospinal fluid hypocretin-1 levels were measured in all individuals using a radio-immunoassay technique. Additionally, eight Parkinson's disease patients without dementia and seven Parkinson's disease patients with dementia underwent video-polysomnogram and multiple sleep latencies test. Epworth sleepiness scale scores were higher in Parkinson's disease patients without dementia and Parkinson's disease patients with dementia than controls (P < 0.01) and scores >10 were more frequent in Parkinson's disease patients with dementia than in Parkinson's disease patients without dementia (P = 0.04). Cerebrospinal fluid hypocretin-1 levels were similar among groups (controls = 321.15 ± 47.15 pg/ml; without dementia = 300.99 ± 58.68 pg/ml; with dementia = 309.94 ± 65.95 pg/ml; P = 0.67), and unrelated to either epworth sleepiness scale or mini-mental state examination. Dominant occipital frequency awake was slower in Parkinson's disease patients with dementia than Parkinson's disease patients without dementia (P = 0.05). Presence of slow dominant occipital frequency and/or loss of normal non-rapid eye movement sleep architecture was more frequent among Parkinson's disease patients with dementia (P = 0.029). Thus, excessive daytime sleepiness is more frequent in Parkinson's disease patients with dementia than Parkinson's disease patients without dementia, but lumbar cerebrospinal fluid hypocretin-1 levels are normal and unrelated to severity of sleepiness or the cognitive status. Lumbar cerebrospinal fluid does not accurately reflect the hypocretin cell loss known to occur in the hypothalamus of advanced Parkinson's disease. Alternatively, mechanisms other than hypocretin cells dysfunction may be responsible for excessive daytime sleepiness and the sleep architecture alterations seen in these patients.

Reply to: Posterior cingulate hypometabolism in early Alzheimer's disease: what is the contribution of local atrophy and disconnection?

Aggleton, J. P. — Sun, 25 Oct 2009 20:59:24 PDT

Posterior cingulate hypometabolism in early Alzheimer's disease: what is the contribution of local atrophy versus disconnection?

Chetelat, G., Villain, N., Desgranges, B., Eustache, F., Baron, J.-C. — Sun, 25 Oct 2009 20:59:24 PDT

Unilateral pedunculopontine stimulation improves falls in Parkinson's disease

Wed, 21 Oct 2009 07:19:57 PDT

Postural instability and falls are a major source of disability in patients with advanced Parkinson's disease. These problems are currently not well addressed by either pharmacotherapy nor by subthalamic nucleus deep-brain stimulation surgery. The neuroanatomical substrates of posture and gait are poorly understood but a number of important observations suggest a major role for the pedunculopontine nucleus and adjacent areas in the brainstem. We conducted a double-blinded evaluation of unilateral pedunculopontine nucleus deep-brain stimulation in a pilot study in six advanced Parkinson's disease patients with significant gait and postural abnormalities. There was no significant difference in the double-blinded on versus off stimulation Unified Parkinson's Disease Rating Scale motor scores after 3 or 12 months of continuous stimulation and no improvements in the Unified Parkinson's Disease Rating Scale part III scores compared to baseline. In contrast, patients reported a significant reduction in falls in the on and off medication states both at 3 and 12 months after pedunculopontine nucleus deep-brain stimulation as captured in the Unified Parkinson's Disease Rating Scale part II scores. Our results suggest that pedunculopontine nucleus deep-brain stimulation may be effective in preventing falls in patients with advanced Parkinson's disease but that further evaluation of this procedure is required.

Clinical features of spinal and bulbar muscular atrophy

Wed, 21 Oct 2009 07:19:50 PDT

Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models.

Cerebellar agenesis revisited

Boyd, C.A.R — Tue, 20 Oct 2009 08:40:28 PDT

New clinical and employment information, together with over-looked previously published information, on a patient (H.C.) is reviewed. H.C., who died at the age of 76 in 1939, was found, by chance during anatomical dissection, to lack a cerebellum. This synthesis challenges an unusual and interesting account of cerebellar agenesis published in Brain in 1994 by Glickstein (see also Glickstein, 2006), in which the allegedly ‘bogus’ oral history of this individual's motor skills was held to have led to ‘medical myth making’. Part of the burden of the 1994 paper was to show that ‘cerebellar agenesis is always associated with profound motor deficits’. Glickstein therefore focussed on an apparent ‘exception’ to this conclusion, concerning the brain of a single case, H.C., who died 70 years ago, who ‘had given rise to an oral tradition alleging that normal movement is possible despite total cerebellar agenesis’. Glickstein (1994) concludes ‘despite an oral tradition to the contrary there is absolutely no evidence about the motor capacities of this man during his life’. Rather remarkably, an extensive history of this individual has become available, its significance becoming noted only this year; this complements and adds to a previous brief history published on H.C. (and not mentioned in the 1994 paper; see below). The new evidence includes the death certificate stating the man's occupation to have been ‘manual labourer’ with all the implications relevant to his supposed incapacity. The written historical record thus confronts the alleged ‘myth’. It is interesting to note how medical records on an undoubtedly very ordinary citizen were recorded in London in the 1930s (before the NHS was set up in 1949) and how they could be made accessible to clinical colleagues in east London in the middle of World War II blitz bombing of the capital.

Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies

Tue, 20 Oct 2009 08:40:26 PDT

Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8–13.2; ² = 26.7; 1 degree of freedom; P = 2.4 x 10^–7). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8–13.2; P = 4.2 x 10^–4) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3–74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.

Cerebral oxygen and glucose metabolism in patients with mitochondrial m.3243A>G mutation

Tue, 20 Oct 2009 08:40:25 PDT

The m.3243A>G mutation is the most common pathogenic mutation in mitochondrial DNA. It leads to defective oxidative phosphorylation, decreased oxygen consumption and increased glucose utilization and lactate production in vitro. However, oxygen and glucose metabolism has not been studied in the brain of patients harbouring the m.3243A>G mutation. Therefore, 14 patients with the m.3243A>G mutation, not experiencing acute stroke-like episodes and 14 age-matched controls underwent positron emission tomography using 2-[¹⁸F]fluoro-2-deoxyglucose, [¹⁵O]H₂O and [¹⁵O]O₂ as the tracers during normoglycaemia. The metabolic rate of oxygen and glucose were determined using a quantitative region of interest analysis. Metabolites in unaffected periventricular tissue were measured using magnetic resonance spectroscopy. We found that the cerebral metabolic rate of oxygen was decreased by 26% (range 18%–29%) in the grey as well as the white matter of patients with the m.3243A>G mutation. A decrease in the metabolic rate of glucose was found with predilection to the posterior part of the brain. No major changes were detected in cerebral blood flow or the number of white matter lesions. Our results show that the m.3243A>G mutation leads to a global decrease in oxygen consumption in the grey matter including areas where no other signs of disease were present.

Ectopic expression of polysialylated neural cell adhesion molecule in adult macaque Schwann cells promotes their migration and remyelination potential in the central nervous system

Bachelin, C., Zujovic, V., Buchet, D., Mallet, J., Baron-Van Evercooren, A. — Tue, 20 Oct 2009 08:40:24 PDT

Recent findings suggested that inducing neural cell adhesion molecule polysialylation in rodents is a promising strategy for promoting tissue repair in the injured central nervous system. Since autologous grafting of Schwann cells is one potential strategy to promote central nervous system remyelination, it is essential to show that such a strategy can be translated to adult primate Schwann cells and is of interest for myelin diseases. Adult macaque Schwann cells were transduced with a lentiviral vector encoding sialyltransferase, an enzyme responsible for neural cell adhesion molecule polysialylation. In vitro, we found that ectopic expression of polysialylate promoted adult macaque Schwann cell migration and improved their integration among astrocytes in vitro without modifying their antigenic properties as either non-myelinating or pro-myelinating. In addition, forced expression of polysialylate in adult macaque Schwann cells decreased their adhesion with sister cells. To investigate the ability of adult macaque Schwann cells to integrate and migrate in vivo, focally induced demyelination was targeted to the spinal cord dorsal funiculus of nude mice, and both control and sialyltransferase expressing Schwann cells overexpressing green fluorescein protein were grafted remotely from the lesion site. Analysis of the spatio-temporal distribution of the grafted Schwann cells performed in toto and in situ, showed that in both groups, Schwann cells migrated towards the lesion site. However, migration of sialyltransferase expressing Schwann cells was more efficient than that of control Schwann cells, leading to their accelerated recruitment by the lesion. Moreover, ectopic expression of polysialylated neural cell adhesion molecule promoted adult macaque Schwann cell interaction with reactive astrocytes when exiting the graft, and their ‘chain-like’ migration along the dorsal midline. The accelerated migration of sialyltransferase expressing Schwann cells to the lesion site enhanced their ability to compete for myelin repair with endogenous cells, while control Schwann cells were unable to do so. Finally, remyelination by the exogenous sialyltransferase expressing Schwann cells restored the normal distribution of paranodal and nodal elements on the host axons. These greater performances of sialyltransferase expressing Schwann cell correlated with their sustained expression of polysialylated neural cell adhesion molecule at early times when migrating from the graft to the lesion, and its progressive downregulation at later times during remyelination. These results underline the potential therapeutic benefit to genetically modify Schwann cells to overcome their poor migration capacity and promote their repair potential in demyelinating disorders of the central nervous system.

A milestone in three millennia of epileptology--the centenary of the International League against Epilepsy

Eadie, M. — Tue, 20 Oct 2009 08:40:21 PDT

Markers of neurodegeneration in idiopathic rapid eye movement sleep behaviour disorder and Parkinson's disease

Postuma, R. B., Gagnon, J. F., Vendette, M., Montplaisir, J. Y. — Tue, 20 Oct 2009 08:40:20 PDT

Idiopathic rapid eye movement sleep behaviour disorder is an important risk factor in the development of Parkinson's disease. Numerous potential predictive markers of Parkinson's disease may present before motor symptoms emerge, but testing of these markers in rapid eye movement sleep behaviour disorder has been performed only in small studies. There has been no comparison of markers between patients with idiopathic rapid eye movement sleep behaviour disorder and Parkinson's disease, and between men and women. We evaluated an array of potential Parkinson's disease predictive markers in 159 patients; including 68 with idiopathic rapid eye movement sleep behaviour disorder, 36 controls, 34 Parkinson's patients with rapid eye movement sleep behaviour disorder and 21 Parkinson's patients without rapid eye movement sleep behaviour disorder. Compared with controls, patients with idiopathic rapid eye movement sleep behaviour disorder demonstrated substantial olfactory loss (P < 0.001). Olfaction was more impaired in Parkinson's disease than idiopathic rapid eye movement sleep behaviour disorder and did not differ between Parkinson's patients with, or without, rapid eye movement sleep behaviour disorder. Numerous measures of motor function including the Unified Parkinson Disease Rating Scale alternate tap, Purdue Peg Board and Timed ’Up and Go‘ were impaired in idiopathic rapid eye movement sleep behaviour disorder compared with controls (P < 0.01). All of these motor measures were worse with Parkinson's disease than with idiopathic rapid eye movement sleep behaviour disorder, regardless of rapid eye movement sleep behaviour disorder status. Autonomic symptoms and systolic blood pressure drop were impaired in patients with idiopathic rapid eye movement sleep behaviour disorder compared with controls (P = 0.003). Orthostatic abnormalities in Parkinson's disease were found in the group with rapid eye movement sleep behaviour disorder (P < 0.001). However, Parkinson's patients without rapid eye movement sleep behaviour disorder were not different than controls and had less impairment than those with idiopathic rapid eye movement sleep behaviour disorder (P = 0.004) and Parkinson's patients with rapid eye movement sleep behaviour disorder (P < 0.001). Colour vision was impaired in idiopathic rapid eye movement sleep behaviour disorder compared with controls (P < 0.001). However, only Parkinson's patients with rapid eye movement sleep behaviour disorder had abnormalities significantly different than controls (P < 0.001), and there were significant differences between Parkinson's patients with or without rapid eye movement sleep behaviour disorder (P < 0.04). Idiopathic rapid eye movement sleep behaviour disorder patients had slightly increased harm avoidance scores on personality testing (P = 0.04). Other than slightly better performances among women in the Purdue Peg Board, there was no difference in any measure between men and women, suggesting similar pathogenic processes underlying rapid eye movement sleep behaviour disorder. Patients with idiopathic rapid eye movement sleep behaviour disorder demonstrate abnormalities in numerous potential markers of neurodegenerative disease—these markers are heterogeneous, generally correlate with each other and occur equally in men and women. Although these abnormalities are usually intermediate between control values and Parkinson's patients, autonomic dysfunction and colour vision appear to be more linked to rapid eye movement sleep behaviour disorder status than Parkinson's disease, suggesting a unique pathophysiology of these abnormalities.

Integration of gaze direction and facial expression in patients with unilateral amygdala damage

Cristinzio, C., N'Diaye, K., Seeck, M., Vuilleumier, P., Sander, D. — Wed, 14 Oct 2009 05:32:11 PDT

Affective and social processes play a major role in everyday life, but appropriate methods to assess disturbances in these processes after brain lesions are still lacking. Past studies have shown that amygdala damage can impair recognition of facial expressions, particularly fear, as well as processing of gaze direction; but the mechanisms responsible for these deficits remain debated. Recent accounts of human amygdala function suggest that it is a critical structure involved in self-relevance appraisal. According to such accounts, responses to a given facial expression may vary depending on concomitant gaze direction and perceived social meaning. Here we investigated facial emotion recognition and its interaction with gaze in patients with unilateral amygdala damage (n = 19), compared to healthy controls (n = 10), using computer-generated dynamic face stimuli expressing variable intensities of fear, anger or joy, with different gaze directions (direct versus averted). If emotion perception is influenced by the self-relevance of expression based on gaze direction, a fearful face with averted gaze should be more relevant than the same expression with direct gaze because it signals danger near the observer; whereas anger with direct gaze should be more relevant than with averted gaze because it directly threatens the observer. Our results confirm a critical role for the amygdala in self-relevance appraisal, showing an interaction between gaze and emotion in healthy controls, a trend for such interaction in left-damaged patients but not in right-damaged patients. Impaired expression recognition was generally more severe for fear, but with a greater deficit for right versus left damage. These findings do not only provide new insights on human amygdala function, but may also help design novel neuropsychological tests sensitive to amygdala dysfunction in various patient populations.

Notch-1 signalling is activated in brain arteriovenous malformations in humans

Wed, 07 Oct 2009 06:25:12 PDT

A role for the Notch signalling pathway in the formation of arteriovenous malformations during development has been suggested. However, whether Notch signalling is involved in brain arteriovenous malformations in humans remains unclear. Here, we performed immunohistochemistry on surgically resected brain arteriovenous malformations and found that, compared with control brain vascular tissue, Notch-1 signalling was activated in smooth muscle and endothelial cells of the lesional tissue. Western blotting showed an activated form of Notch-1 in brain arteriovenous malformations, irrespective of clinical presentation and with or without preoperative embolization, but not in normal cerebral vessels from controls. In addition, the Notch-1 ligands Jagged-1 and Delta-like-4 and the downstream Notch-1 target Hes-1 were increased in abundance and activated in human brain arteriovenous malformations. Finally, increased angiogenesis was found in adult rats treated with a Notch-1 activator. Our findings suggest that activation of Notch-1 signalling is a phenotypic feature of brain arteriovenous malformations, and that activation of Notch-1 in normal vasculature induces a pro-angiogenic state, which may contribute to the development of vascular malformations.

Relating visual to verbal semantic knowledge: the evaluation of object recognition in prosopagnosia

Barton, J. J. S., Hanif, H., Ashraf, S. — Mon, 05 Oct 2009 07:59:24 PDT

Assessment of face specificity in prosopagnosia is hampered by difficulty in gauging pre-morbid expertise for non-face object categories, for which humans vary widely in interest and experience. In this study, we examined the correlation between visual and verbal semantic knowledge for cars to determine if visual recognition accuracy could be predicted from verbal semantic scores. We had 33 healthy subjects and six prosopagnosic patients first rated their own knowledge of cars. They were then given a test of verbal semantic knowledge that presented them with the names of car models, to which they were to match the manufacturer. Lastly, they were given a test of visual recognition, presenting them with images of cars to which they were to provide information at three levels of specificity: model, manufacturer and decade of make. In controls, while self-ratings were only moderately correlated with either visual recognition or verbal semantic knowledge, verbal semantic knowledge was highly correlated with visual recognition, particularly for more specific levels of information. Item concordance showed that less-expert subjects were more likely to provide the most specific information (model name) for the image when they could also match the manufacturer to its name. Prosopagnosic subjects showed reduced visual recognition of cars after adjusting for verbal semantic scores. We conclude that visual recognition is highly correlated with verbal semantic knowledge, that formal measures of verbal semantic knowledge are a more accurate gauge of expertise than self-ratings, and that verbal semantic knowledge can be used to adjust tests of visual recognition for pre-morbid expertise in prosopagnosia.

Semantic dementia: demography, familial factors and survival in a consecutive series of 100 cases

Mon, 05 Oct 2009 07:59:19 PDT

A great deal has been written about cognitive aspects of semantic dementia but little is known about the demography or prognosis. We describe these features in a consecutive series of 100 patients seen over a 17-year period; all cases were assessed and followed up in a specialist clinic. The mean age at diagnosis was 64.2 (±7.1) range 40–79 years, but 46 presented after age 65 and 7 after 75; a higher proportion than the existing literature might predict. Fifteen had a first-degree relative with dementia, but in seven this was almost certainly unrelated. Only two had relatives with young-onset dementia. There were no families with more than two affected members. The familial rate was estimated at between 2% and 7% (95% confidence interval 0–12%). Kaplan–Meier analyses indicated a 50% survival of 12.8 years (95% confidence interval 11.9–13.7); a more benign course than suggested by neuropathologically based studies. We were unable to identify any factors influencing survival. Of the 100, 34 have died, with pathological confirmation in 24; 18 had frontotemporal lobar degeneration with ubiquitin-positive inclusions (13 of 13 confirmed TAR DNA binding protein-43 positive), and 3 had classic tau-positive Pick bodies and 3 had Alzheimer's pathology. The age at diagnosis or death across the pathological subgroups was equivalent. Although semantic dementia has a strong statistical association with ubiquitin-positive pathology, it does not have the signature of familial frontotemporal lobar degeneration with ubiquitin-positive inclusions, notably the presence of intranuclear lentiform TAR DNA binding protein-43 inclusions. The age of onset is older than predicted and the course more slowly progressive than suggested by earlier studies of small groups of subjects.

Non-verbal sound processing in the primary progressive aphasias

Thu, 01 Oct 2009 04:30:40 PDT

Little is known about the processing of non-verbal sounds in the primary progressive aphasias. Here, we investigated the processing of complex non-verbal sounds in detail, in a consecutive series of 20 patients with primary progressive aphasia [12 with progressive non-fluent aphasia; eight with semantic dementia]. We designed a novel experimental neuropsychological battery to probe complex sound processing at early perceptual, apperceptive and semantic levels, using within-modality response procedures that minimized other cognitive demands and matching tests in the visual modality. Patients with primary progressive aphasia had deficits of non-verbal sound analysis compared with healthy age-matched individuals. Deficits of auditory early perceptual analysis were more common in progressive non-fluent aphasia, deficits of apperceptive processing occurred in both progressive non-fluent aphasia and semantic dementia, and deficits of semantic processing also occurred in both syndromes, but were relatively modality specific in progressive non-fluent aphasia and part of a more severe generic semantic deficit in semantic dementia. Patients with progressive non-fluent aphasia were more likely to show severe auditory than visual deficits as compared to patients with semantic dementia. These findings argue for the existence of core disorders of complex non-verbal sound perception and recognition in primary progressive aphasia and specific disorders at perceptual and semantic levels of cortical auditory processing in progressive non-fluent aphasia and semantic dementia, respectively.

Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease

Tue, 22 Sep 2009 07:46:33 PDT

Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year follow-up. A double-blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by low-frequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk–benefit ratio.

Neuronal correlates of functional magnetic resonance imaging in human temporal cortex

Tue, 22 Sep 2009 07:46:31 PDT

The relationship between changes in functional magnetic resonance imaging and neuronal activity remains controversial. Data collected during awake neurosurgical procedures for the treatment of epilepsy provided a rare opportunity to examine this relationship in human temporal association cortex. We obtained functional magnetic resonance imaging blood oxygen dependent signals, single neuronal activity and local field potentials from 8 to 300 Hz at 13 temporal cortical sites, from nine subjects, during paired associate learning and control measures. The relation between the functional magnetic resonance imaging signal and the electrophysiologic parameters was assessed in two ways: colocalization between significant changes in these signals on the same paired associate-control comparisons and multiple linear regressions of the electrophysiologic measures on the functional magnetic resonance imaging signal, across all tasks. Significant colocalization was present between increased functional magnetic resonance imaging signals and increased local field potentials power in the 50–250 Hz range. Local field potentials power greater than 100 Hz was also a significant regressor for the functional magnetic resonance imaging signal, establishing this local field potentials frequency range as a neuronal correlate of the functional magnetic resonance imaging signal. There was a trend for a relation between power in some low frequency local field potentials frequencies and the functional magnetic resonance imaging signal, for 8–15 Hz increases in the colocalization analysis and 16–23 Hz in the multiple linear regression analysis. Neither analysis provided evidence for an independent relation to frequency of single neuron activity.

Language networks in semantic dementia

Wed, 16 Sep 2009 08:25:24 PDT

Cognitive deficits in semantic dementia have been attributed to anterior temporal lobe grey matter damage; however, key aspects of the syndrome could be due to altered anatomical connectivity between language pathways involving the temporal lobe. The aim of this study was to investigate the left language-related cerebral pathways in semantic dementia using diffusion tensor imaging-based tractography and to combine the findings with cortical anatomical and functional magnetic resonance imaging data obtained during a reading activation task. The left inferior longitudinal fasciculus, arcuate fasciculus and fronto-parietal superior longitudinal fasciculus were tracked in five semantic dementia patients and eight healthy controls. The left uncinate fasciculus and the genu and splenium of the corpus callosum were also obtained for comparison with previous studies. From each tract, mean diffusivity, fractional anisotropy, as well as parallel and transverse diffusivities were obtained. Diffusion tensor imaging results were related to grey and white matter atrophy volume assessed by voxel-based morphometry and functional magnetic resonance imaging activations during a reading task. Semantic dementia patients had significantly higher mean diffusivity, parallel and transverse in the inferior longitudinal fasciculus. The arcuate and uncinate fasciculi demonstrated significantly higher mean diffusivity, parallel and transverse and significantly lower fractional anisotropy. The fronto-parietal superior longitudinal fasciculus was relatively spared, with a significant difference observed for transverse diffusivity and fractional anisotropy, only. In the corpus callosum, the genu showed lower fractional anisotropy compared with controls, while no difference was found in the splenium. The left parietal cortex did not show significant volume changes on voxel-based morphometry and demonstrated normal functional magnetic resonance imaging activation in response to reading items that stress sublexical phonological processing. This study shows that semantic dementia is associated with anatomical damage to the major superior and inferior temporal white matter connections of the left hemisphere likely involved in semantic and lexical processes, with relative sparing of the fronto-parietal superior longitudinal fasciculus. Fronto-parietal regions connected by this tract were activated normally in the same patients during sublexical reading. These findings contribute to our understanding of the anatomical changes that occur in semantic dementia, and may further help to explain the dissociation between marked single-word and object knowledge deficits, but sparing of phonology and fluency in semantic dementia.

Reply: Timing of brain damage and verbal-performance IQ tilts

Fri, 11 Sep 2009 02:56:52 PDT

Timing of brain damage and verbal-performance IQ tilts

Gordon, A. G. — Fri, 11 Sep 2009 02:56:52 PDT

A type I interferon signature in monocytes is associated with poor response to interferon-{beta} in multiple sclerosis

Wed, 09 Sep 2009 08:09:22 PDT

The effect of interferon-beta in multiple sclerosis is modest and many patients do not respond to treatment. To date, no single biomarker reliably correlates with responsiveness to interferon-β in multiple sclerosis. In the present study, genome-wide expression profiling was performed in peripheral blood mononuclear cells from 47 multiple sclerosis patients treated with interferon-β for a minimum of 2 years and classified as responders and non-responders based on clinical criteria. A validation cohort of 30 multiple sclerosis patients was included in the study to replicate gene-expression findings. Before treatment, interferon-β responders and non-responders were characterized by differential expression of type I interferon-induced genes with overexpression of the type interferon-induced genes in non-responders. Upon treatment the expression of these genes remained unaltered in non-responders, but was strongly upregulated in responders. Functional experiments showed a selective increase in phosphorylated STAT1 levels and interferon receptor 1 expression in monocytes of non-responders at baseline. When dissecting this type I interferon signature further, interferon-β non-responders were characterized by increased monocyte type I interferon secretion upon innate immune stimuli via toll-like receptor 4, by increased endogenous production of type I interferon, and by an elevated activation status of myeloid dendritic cells. These findings indicate that perturbations of the type I interferon signalling pathway in monocytes are related to lack of response to interferon-β, and type I interferon-regulated genes may be used as response markers in interferon-β treatment.

Diffusion-weighted brain imaging study of patients with clinical diagnosis of corticobasal degeneration, progressive supranuclear palsy and Parkinson's disease

Lodi, R. — Mon, 31 Aug 2009 06:55:15 PDT

Erratum

Thu, 20 Aug 2009 22:27:28 PDT

The Culture of Insomnia

Parkes, J. D. — Wed, 19 Aug 2009 22:50:12 PDT

Corrigendum

Wed, 12 Aug 2009 08:25:38 PDT

Epstein-Barr virus infection is not a characteristic feature of multiple sclerosis brain

Tue, 28 Jul 2009 08:53:35 PDT

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system (CNS) that is thought to be caused by a combination of genetic and environmental factors. To date, considerable evidence has associated Epstein–Barr virus (EBV) infection with disease development. However, it remains controversial whether EBV infects multiple sclerosis brain and contributes directly to CNS immunopathology. To assess whether EBV infection is a characteristic feature of multiple sclerosis brain, a large cohort of multiple sclerosis specimens containing white matter lesions (nine adult and three paediatric cases) with a heterogeneous B cell infiltrate and a second cohort of multiple sclerosis specimens (12 cases) that included B cell infiltration within the meninges and parenchymal B cell aggregates, were examined for EBV infection using multiple methodologies including in situ hybridization, immunohistochemistry and two independent real-time polymerase chain reaction (PCR) methodologies that detect genomic EBV or the abundant EBV encoded RNA (EBER) 1, respectively. We report that EBV could not be detected in any of the multiple sclerosis specimens containing white matter lesions by any of the methods employed, yet EBV was readily detectable in multiple Epstein–Barr virus-positive control tissues including several CNS lymphomas. Furthermore, EBV was not detected in our second cohort of multiple sclerosis specimens by in situ hybridization. However, our real-time PCR methodologies, which were capable of detecting very few EBV infected cells, detected EBV at low levels in only 2 of the 12 multiple sclerosis meningeal specimens examined. Our finding that CNS EBV infection was rare in multiple sclerosis brain indicates that EBV infection is unlikely to contribute directly to multiple sclerosis brain pathology in the vast majority of cases.

Corrigendum

Thu, 21 May 2009 09:23:12 PDT

Impaired small-world efficiency in structural cortical networks in multiple sclerosis associated with white matter lesion load

He, Y., Dagher, A., Chen, Z., Charil, A., Zijdenbos, A., Worsley, K., Evans, A. — Tue, 12 May 2009 22:22:34 PDT

White matter tracts, which play a crucial role in the coordination of information flow between different regions of grey matter, are particularly vulnerable to multiple sclerosis. Many studies have shown that the white matter lesions in multiple sclerosis are associated with focal abnormalities of grey matter, but little is known about the alterations in the coordinated patterns of cortical morphology among regions in the disease. Here, we used cortical thickness measurements from structural magnetic resonance imaging to investigate the relationship between the white matter lesion load and the topological efficiency of structural cortical networks in multiple sclerosis. Network efficiency was defined using a ‘small-world’ network model that quantifies the effectiveness of information transfer within brain networks. In this study, we first classified patients (n = 330) into six subgroups according to their total white matter lesion loads, and identified structural brain networks for each multiple sclerosis group by thresholding the corresponding inter-regional cortical thickness correlation matrix, followed by a network efficiency analysis with graph theoretical approaches. The structural cortical networks in multiple sclerosis demonstrated efficient small-world architecture regardless of the lesion load, an organization that maximizes the information processing at a relatively low wiring cost. However, we found that the overall small-world network efficiency in multiple sclerosis was significantly disrupted in a manner proportional to the extent of total white matter lesions. Moreover, regional efficiency was also significantly decreased in specific brain regions, including the insula and precentral gyrus as well as regions of prefrontal and temporal association cortices. Finally, we showed that the lesions also altered many cortical thickness correlations in the frontal, temporal and parietal lobes. Our results suggest that the white matter lesions in multiple sclerosis might be associated with aberrant neuronal connectivity among widely distributed brain regions, and provide structural (morphological) evidence for the notion of multiple sclerosis as a disconnection syndrome.

Neurobiological mechanisms underlying emotional processing in relapsing-remitting multiple sclerosis

Wed, 06 May 2009 07:00:55 PDT

Affective disorders are frequent and disabling conditions in multiple sclerosis; however, the underlying neurobiological mechanisms are still poorly understood and investigated. Previous structural imaging studies have suggested that damage of frontal and temporal cortices plays an important role in the genesis of emotional disorders in multiple sclerosis, although psychosocial factors have been also implicated. However, this initial research may not have fully characterized the brain's functional dynamics of emotional processes in multiple sclerosis. Functional magnetic resonance imaging (fMRI) appears, therefore, to be a sensible tool to explore neurobiological mechanisms of emotions in multiple sclerosis since it also allows investigation of the functional connectivity or ‘communication’ between critical regions in affective behaviour [e.g. the prefrontal cortex (PFC) and amygdala]. In the present study, functional imaging was used to investigate the neural substrate of processing emotions in 12 multiple sclerosis patients relative to 12 healthy subjects matched for age and educational level. Only relapsing-remitting multiple sclerosis patients, who were cognitively unimpaired and who did not assume disease-modifying therapies, were included, given the potential confounding effect of these variables in the genesis of emotional symptoms. Brain responses were recorded in all participants while they executed an active task that consisted of processing emotional relative to neutral stimuli. Structural measures (i.e. total lesion load, grey matter, white matter and total brain volume) were also recorded to control for any effect of these variables. Despite similar performances during the task, and no differences in structural measures, multiple sclerosis patients displayed significantly greater responses within the ventrolateral PFC [t's > 5, P's < 0.02, Family Wise Error (FWE), small volume correction (svc)], compared to controls. Multiple sclerosis patients also showed a lack of functional connectivity between two prefrontal areas and the amygdala, a subcortical region critically involved in the generation of negative feelings (t's > 4, P's < 0.05, FWE, svc). It is likely that pathological changes related to the disease are reflected in an abnormal ‘communication’ between key emotional regions and that adaptive processes take place and become evident as enhanced responses of task-specific areas (i.e. the ventrolateral PFC). Local reorganizations in the brain can be viewed as compensatory mechanisms aimed to limit the clinical expression of emotional symptoms in multiple sclerosis. Overall our findings offer new insights into the neurobiological mechanisms of emotions in multiple sclerosis and provide evidence that they resemble those described for some psychiatric disorders.

Corrigendum

Thu, 24 Jul 2008 01:23:30 PDT

Selective impairment of hand mental rotation in patients with focal hand dystonia

Fiorio, M., Tinazzi, M., Aglioti, S. M. — Wed, 25 May 2005 04:19:44 PDT