Brain - Advance Access

Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis

Vucic, S., Nicholson, G. A., Kiernan, M. C. — 2008-05-09

Familial amyotrophic lateral sclerosis (FALS) is an inherited neurodegenerative disorder of the motor neurons. While 10–15% of cases are caused by mutations in the copper/zinc superoxide-dismutase-1 (SOD-1) gene, the dying-forward hypothesis, in which corticomotoneurons induce anterograde excitotoxic motoneuron degeneration, has been proposed as a potential mechanism. The present study applied novel threshold tracking transcranial magnetic stimulation techniques to investigate the mechanisms underlying neurodegeneration in FALS. Studies were undertaken in 14 asymptomatic and 3 pre-symptomatic SOD-1 mutation carriers, followed longitudinally for up to 3-years. The pre-symptomatic subjects were asymptomatic at the time of their initial study but developed symptoms during the follow-up period. Results were compared to 7 SOD-1 FALS patients, 50 sporadic ALS patients and 55 normal controls. Short-interval intracortical inhibition (SICI) was significantly reduced in SOD-1 FALS (–1.2 ± 0.6%) and sporadic ALS patients (–0.7 ± 0.3%) compared to asymptomatic SOD-1 mutation carriers (9.8 ± 1.5%, P<0.00001) and normal controls (8.5 ± 1.0%, P<0.00001). SICI reduction was accompanied by increases in intracortical facilitation, motor evoked potential amplitudes and the slope of the magnetic stimulus-response curve. In two pre-symptomatic SOD-1 mutation carriers SICI was completely absent (SICI patient 1, –3.2%; patients 2, –1.3%), while in one subject there was a 32% reduction in SICI prior to symptom onset. These three individuals subsequently developed clinical features of ALS. Simultaneous investigation of central and peripheral excitability has established that cortical hyperexcitability develops in clinically affected SOD-1 FALS patients, similar to that seen in sporadic ALS patients, thereby suggesting that a similar pathophysiological process in evident in both familial and sporadic ALS patients. In addition, the present study has established that cortical hyperexcitability precedes the development of clinical symptoms in pre-symptomatic carriers of the SOD1 mutation, thereby suggesting that cortical hyperexcitability underlies neurodegeneration in FALS.

Changes in connectivity after visual cortical brain damage underlie altered visual function

Bridge, H., Thomas, O., Jbabdi, S., Cowey, A. — 2008-05-09

The full extent of the brain's ability to compensate for damage or changed experience is yet to be established. One question particularly important for evaluating and understanding rehabilitation following brain damage is whether recovery involves new and aberrant neural connections or whether any change in function is due to the functional recruitment of existing pathways, or both. Blindsight, a condition in which subjects with complete destruction of part of striate cortex (V1) retain extensive visual capacities within the clinically blind field, is an excellent example of altered visual function. Since the main pathway to the visual cortex is destroyed, the spared or recovered visual ability must arise from either an existing alternative pathway, or the formation of a new pathway. Using diffusion-weighted MRI, we show that both controls and blindsight subject GY, whose left V1 is destroyed, show an ipsilateral pathway between LGN (lateral geniculate nucleus) and human motion area MT+/V5 (bypassing V1). However, in addition, GY shows two major features absent in controls: (i) a contralateral pathway from right LGN to left MT+/V5, (ii) a substantial cortico-cortical connection between MT+/V5 bilaterally. Both observations are consistent with previous functional MRI data from GY showing enhanced ipsilateral activation in MT+/V5. There is also evidence for a pathway in GY from left LGN to right MT+/V5, although the lesion makes its quantification difficult. This suggests that employing alternative brain regions for processing of information following cortical damage in childhood may strengthen or establish specific connections.

Stereotactic localization of the human pedunculopontine nucleus: atlas-based coordinates and validation of a magnetic resonance imaging protocol for direct localization

2008-05-08

The pedunculopontine nucleus (PPN) is a promising new target for deep brain stimulation (DBS) in parkinsonian patients with gait disturbance and postural instability refractory to other treatment modalities. This region of the brain is unfamiliar territory to most functional neurosurgeons. This paper reviews the anatomy of the human PPN and describes novel, clinically relevant methods for the atlas-based and MRI-based localization of the nucleus. These two methods of PPN localization are evaluated and compared on stereotactic MRI data acquired from a diverse group of 12 patients undergoing implantation of deep brain electrodes at sites other than the PPN. Atlas-based coordinates of the rostral and caudal PPN poles in relation to fourth ventricular landmarks were established by amalgamating information sourced from two published human brain atlases. These landmarks were identified on acquired T1 images and atlas-derived coordinates used to plot the predicted PPN location on all 24 sides. Images acquired using a specifically modified, proton-density MRI protocol were available for each patient and were spatially fused to the T1 images. This widely available and rapid protocol provided excellent definition between gray and white matter within the region of interest. Together with an understanding of the regional anatomy, direct localization of the PPN was possible on all 24 sides. The coordinates for each directly localized nucleus were measured in relation to third and fourth ventricular landmarks. The mean (SD) of the directly localized PPN midpoints was 6.4 mm (0.5) lateral, 3.5 mm (1.0) posterior and 11.4 mm (1.2) caudal to the posterior commissure in the anterior commissure–posterior commissure plane. For the directly localized nucleus, there was similar concordance for the rostral pole of the PPN in relation to third and fourth ventricular landmarks (P>0.05). For the caudal PPN pole, fourth ventricular landmarks provided greater concordance with reference to the anteroposterior coordinate (P<0.001). There was a significant difference between localization of the PPN poles as predicted by atlas-based coordinates and direct MRI localization. This difference affected mainly the rostrocaudal coordinates; the mean lateral and anteroposterior coordinates of the directly localized PPN poles were within 0.5 mm of the atlas-based predicted values. Our findings provide simple, rapid and precise methods that are of clinical relevance to the atlas-based and direct stereotactic localization of the human PPN. Direct MRI localization may allow greater individual accuracy than that afforded by atlas-based coordinates when localizing the human PPN and may be relevant to groups evaluating the clinical role of PPN DBS.

The merest Logomachy: The 1868 Norwich discussion of aphasia by Hughlings Jackson and Broca

Lorch, M. P. — 2008-04-03

No subject of late years has so occupied the attention of physiologists in all parts of the world, as the attempt to localise the grand attribute of humanity, the faculty of speech.

(Bateman, 1870, p. 178)

This article reconsiders the events that took place at the 1868 meeting of the British Association for the Advancement of Science (BA) in Norwich. Paul Broca and John Hughlings Jackson were invited to speak on the new and controversial subject of aphasia. Over the ensuing decades, there have been repeated references made to a debate between Broca and Jackson. This meeting has been identified as a turning point in favour of Broca's position on the cerebral localization of language. A return to original sources from key witnesses reveals that the opinion of the British practitioners was generally against Broca's views. Close examination of contemporaneous materials suggests that no public debate between Jackson and Broca occurred. However, the public discussion after Broca's presentation records notable concerns over both theoretical issues of localization of function and the status of exceptional clinical cases. A significant stage in the development of current views on the organization of language in the brain is revealed in the accounts of the BA meeting in August 1868 and successive responses to these events in the British press over a period of years.

Distinct mechanisms of impairment in cognitive ageing and Alzheimer's disease

Mapstone, M., Dickerson, K., Duffy, C. J. — 2008-04-02

Similar manifestations of functional decline in ageing and Alzheimer's disease obscure differences in the underlying cognitive mechanisms of impairment. We sought to examine the contributions of top-down attentional and bottom-up perceptual factors to visual self-movement processing in ageing and Alzheimer's disease. We administered a novel heading discrimination task requiring subjects to determine direction of simulated self-movement from left or right offset optic flow fields of several sizes (25°, 40° or 60° in diameter) to 18 Alzheimer's disease subjects (mean age = 75.3, 55% female), 21 older adult control subjects (mean age = 72.4, 67% female), and 26 younger control subjects (mean age = 26.5, 63% female). We also administered computerized measures of processing speed and divided and selective attention, and psychophysical measures of visual motion perception to all subjects. Both older groups showed significant difficulty in judging the direction of virtual self-movement [F(2,194) = 40.5, P < 0.001] and optic flow stimulus size had little effect on heading discrimination for any group. Both older groups showed impairments on measures of divided [F(2,62) = 22.2, P < 0.01] and selective [F(2,62) = 63.0, P < 0.001] attention relative to the younger adult control group, while the Alzheimer's disease group showed a selective impairment in outward optic flow perception [F(2,64) = 6.3, P = 0.003] relative to both control groups. Multiple linear regression revealed distinct attentional and perceptual contributions to heading discrimination performance for the two older groups. In older adult control subjects, poorer heading discrimination was attributable to attentional deficits (R² adj = 0.41, P = 0.001) whereas, in Alzheimer's disease patients, it was largely attributable to deficits of visual motion perception (R² adj = 0.57, P < 0.001). These findings suggest that successive attentional and perceptual deficits play independent roles in the progressive functional impairments of ageing and Alzheimer's disease. We speculate that the attentional deficits that dominate in older adults may promote the development of the perceptual deficits that further constrain performance in Alzheimer's disease.

Dorsomedial SCN neuronal subpopulations subserve different functions in human dementia

2008-03-27

The suprachiasmatic nuclei (SCN) are necessary and sufficient for the maintenance of circadian rhythms in primate and other mammalian species. The human dorsomedial SCN contains populations of non-species-specific vasopressin and species-specific neurotensin neurons. We made time-series recordings of core body temperature and locomotor activity in 19 elderly, male, end-stage dementia patients and 8 normal elderly controls. Following the death of the dementia patients, neuropathological diagnostic information and tissue samples from the hypothalamus were obtained. Hypothalamic tissue was also obtained from eight normal control cases that had not had activity or core temperature recordings previously. Core temperature was analysed for parametric, circadian features, and activity was analysed for non-parametric and parametric circadian features. These indices were then correlated with the degree of degeneration seen in the SCN (glia/neuron ratio) and neuronal counts from the dorsomedial SCN (vasopressin, neurotensin). Specific loss of SCN neurotensin neurons was associated with loss of activity and temperature amplitude without increase in activity fragmentation. Loss of SCN vasopressin neurons was associated with increased activity fragmentation but not loss of amplitude. Evidence for a circadian rhythm of vasopressinergic activity was seen in the dementia cases but no evidence was seen for a circadian rhythm in neurotensinergic activity. These results provide evidence that the SCN is necessary for the maintenance of the circadian rhythm in humans, information on the role of neuronal subpopulations in subserving this function and the utility of dementia in elaborating brain–behaviour relationships in the human.

Changes in sensory-evoked synaptic activation of motoneurons after spinal cord injury in man

Norton, J. A., Bennett, D. J., Knash, M. E., Murray, K. C., Gorassini, M. A. — 2008-03-15

Following spinal cord injury (SCI), prolonged muscle spasms are readily triggered by brief sensory stimuli. Animal and indirect human studies have shown that a substantial portion of the depolarization of motoneurons during a muscle spasm comes from the activation of persistent inward currents (PICs). The brief (single pulse) sensory stimuli that trigger the PICs and muscle spasms in chronically spinalized animals evoke excitatory post-synaptic potentials (EPSPs) that are broadened to more than 500 ms, the duration of depolarization required to activate a PIC in the motoneuron. Thus, in humans, we investigated if post-synaptic potentials (PSPs) evoked from brief (<20 ms) sensory stimulation are changed after SCI and if they are broadened to ≥500 ms to more readily activate motoneuron PICs and muscle spasms. To estimate both the shape and duration of PSPs in human subjects we used peristimulus frequencygrams (PSFs), which are plots of the instantaneous firing frequency of tonically active single motor units that are time-locked to the occurrence of the sensory stimulus. PSFs in response to cutaneomuscular stimulation of the medial arch or toe of the foot, a sensory stimulus that readily triggers muscle spasms, were compared between non-injured control subjects and in spastic subjects with chronic (>1 year), incomplete SCI. In non-injured controls, a single shock or brief (<20 ms) train of cutaneomuscular stimulation produced PSFs consisting of a 300 ms increase in firing rate above baseline with an interposed period of reduced firing. Parallel intracellular experiments in motoneurons of adult rats revealed that a 300 ms EPSP with a fast intervening inhibitory PSP (IPSP) reproduced the PSF recorded in non-injured subjects. In contrast, the same brief sensory stimulation in subjects with chronic SCI produced PSFs of comparatively long duration (1200 ms) with no evidence for IPSP activation, as reflected by a lack of reduced firing rates after the onset of the PSF. Thus, unlike non-injured controls, the motoneurons of subjects with chronic SCI are activated by very long periods of pure depolarization from brief sensory activation. It is likely that these second-long EPSPs securely recruit slowly activating PICs in motoneurons that are known to mediate, in large part, the many seconds-long activation of motoneurons during involuntary muscle spasms.

Short-term variations in response distribution to cortical stimulation

2008-03-12

Patterns of responses in the cerebral cortex can vary, and are influenced by pre-existing cortical function, but it is not known how rapidly these variations can occur in humans. We investigated how rapidly response patterns to electrical stimulation can vary in intact human brain. We also investigated whether the type of functional change occurring at a given location with stimulation would help predict the distribution of responses elsewhere over the cortex to stimulation at that given location. We did this by studying cortical afterdischarges following electrical stimulation of the cortex in awake humans undergoing evaluations for brain surgery. Response occurrence and location could change within seconds, both nearby to and distant from stimulation sites. Responses might occur at a given location during one trial but not the next. They could occur at electrodes adjacent or not adjacent to those directly stimulated or to other electrodes showing afterdischarges. The likelihood of an afterdischarge at an individual site after stimulation was predicted by spontaneous electroencephalographic activity at that specific site just prior to stimulation, but not by overall cortical activity. When stimulation at a site interrupted motor, sensory or language function, afterdischarges were more likely to occur at other sites where stimulation interrupted similar functions. These results show that widespread dynamic changes in cortical responses can occur in intact cortex within short periods of time, and that the distribution of these responses depends on local brain states and functional brain architecture at the time of stimulation. Similar rapid variations may occur during normal intracortical communication and may underlie changes in the cortical organization of function. Possibly these variations, and the occurrence and distribution of responses to cortical stimulation, could be predicted. If so, interventions such as stimulation might be used to alter spread of epileptogenic activity, accelerate learning or enhance cortical reorganization after brain injury.

Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease

2008-03-12

The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PiB) binds with high affinity to β-pleated sheet aggregates of the amyloid-β (Aβ) peptide in vitro. The in vivo retention of PiB in brains of people with Alzheimer's disease shows a regional distribution that is very similar to distribution of Aβ deposits observed post-mortem. However, the basis for regional variations in PiB binding in vivo, and the extent to which it binds to different types of Aβ-containing plaques and tau-containing neurofibrillary tangles (NFT), has not been thoroughly investigated. The present study examined 28 clinically diagnosed and autopsy-confirmed Alzheimer's disease subjects, including one Alzheimer's disease subject who had undergone PiB-PET imaging 10 months prior to death, to evaluate region- and substrate-specific binding of the highly fluorescent PiB derivative 6-CN-PiB. These data were then correlated with region-matched Aβ plaque load and peptide levels, [³H]PiB binding in vitro, and in vivo PET retention levels. We found that in Alzheimer's disease brain tissue sections, the preponderance of 6-CN-PiB binding is in plaques immunoreactive to either Aβ42 or Aβ40, and to vascular Aβ deposits. 6-CN-PiB labelling was most robust in compact/cored plaques in the prefrontal and temporal cortices. While diffuse plaques, including those in caudate nucleus and presubiculum, were less prominently labelled, amorphous Aβ plaques in the cerebellum were not detectable with 6-CN-PiB. Only a small subset of NFT were 6-CN-PiB positive; these resembled extracellular ‘ghost’ NFT. In Alzheimer's disease brain tissue homogenates, there was a direct correlation between [³H]PiB binding and insoluble Aβ peptide levels. In the Alzheimer's disease subject who underwent PiB-PET prior to death, in vivo PiB retention levels correlated directly with region-matched post-mortem measures of [³H]PiB binding, insoluble Aβ peptide levels, 6-CN-PiB- and Aβ plaque load, but not with measures of NFT. These results demonstrate, in a typical Alzheimer's disease brain, that PiB binding is highly selective for insoluble (fibrillar) Aβ deposits, and not for neurofibrillary pathology. The strong direct correlation of in vivo PiB retention with region-matched quantitative analyses of Aβ plaques in the same subject supports the validity of PiB-PET imaging as a method for in vivo evaluation of Aβ plaque burden.

Intrinsic neuronal properties control selective targeting of regenerating motoneurons

Franz, C. K., Rutishauser, U., Rafuse, V. F. — 2008-03-11

Despite advances in microsurgical techniques, recovery of motor function after peripheral nerve injury is often poor because many regenerating axons reinnervate inappropriate targets. Consequently, surgical repair must include treatment strategies that improve motor axon targeting. Development of such treatments will require a better understanding of the molecular mechanisms governing selective motor axon targeting. This study used a well-established model of nerve transection and repair to examine (1) whether intrinsic differences exist between different pools of motoneurons after peripheral nerve injury, (2) if such differences regulate selective axon targeting, (3) if regenerating motor axons must express polysialic acid (PSA) in order to preferentially reinnervate muscle and (4) whether brief electrical stimulation improves regeneration accuracy because it increases PSA expression on regenerating axons. We found that different motor pools differentially express PSA after injury and that the capacity to re-express PSA appears to be an intrinsic neuronal property established during development. Second, motoneuron pools not up-regulating PSA did not preferentially reinnervate muscle after injury. Third, brief electrical stimulation of the proximal nerve stump immediately after injury only improved selective motor axon targeting if the motoneurons were capable of up-regulating PSA. Finally, the benefits of stimulation were completely abolished if PSA was removed from the regenerating axons. These results indicate that (1) intrinsic neuronal differences between motor pools must be considered in the development of treatments designed to improve axon targeting and (2) therapeutics aimed at increasing PSA levels on regenerating motor axons may lead to superior functional outcomes.

CNTF, a key factor mediating the beneficial effects of inflammatory reactions in the eye

Fischer, D. — 2008-02-20

John Ruskin's relapsing encephalopathy

Kempster, P.A., Alty, J.E. — 2008-02-20

John Ruskin (1819–1900) is chiefly remembered for his works on painting and architecture, and for his powerful and original prose style. In middle age, he suffered recurring episodes of delirium with visual hallucinations and delusions. At about the same time, his writing developed a disjointed polemical character, with cryptic and intemperate elements that disorientated some readers. The nature of Ruskin's ‘madness’ is a key to understanding his later writing career but the psychiatric explanations given by many of his literary biographers seem unsatisfactory. Ruskin left numerous clues about the illness in his diaries, correspondence and publications. It is likely that he had a relapsing-progressive neurological disorder with neuropsychiatric manifestations. It could have been a fluctuating metabolic or immunological encephalopathy, but the diagnosis that best fits the time course of his illness and the prior history of mood disorder and of migraine with aura is Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). Whatever the pathology, its first effects on frontal lobe function may have actually enhanced Ruskin's creative energy for a long time before stepwise cognitive impairment degraded his ability to write.

Does CNTF mediate the effect of intraocular inflammation on optic nerve regeneration?

Cui, Q., Benowitz, L., Yin, Y. — 2008-02-19

Argyrophilic grain disease

Ferrer, I., Santpere, G., van Leeuwen, F. W. — 2008-01-29

Argyrophilic grain disease (AGD) is a common sporadic neurodegenerative disease of old age characterized by the presence of argyrophilic grains (AGs)—dendritic-derived appendages as revealed with the Golgi method—together with pre-tangle neurons in the limbic system, which accounts for about 5% of all demented cases. AGs and pre-tangle neurons contain hyperphosphorylated 4R tau. This is associated with a typical 64 kDa and 68 kDa pattern, but also accompanied by tau truncated forms of low molecular mass, probably resulting from thrombin-mediated proteolysis. Hyperphosphorylated tau also accumulates in oligodendroglial-coiled bodies and in limbic astrocytes. Ballooning neurons in the amygdala are non-specific accompanying abnormalities. A new proposal for AG distribution considers four stages. Clinical symptoms largely depend on the extension of AGs together with the very common associated tauopathies, mainly Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and synucleinopathies. Pathogenesis of AG and related lesions herein proposed includes oxidative stress that is followed by increased expression of oxidative response markers, and activation of stress kinases (stress activated protein kinase and p38). These kinases together with glycogen synthase kinase 3β co-localize with hyperphosphorylated tau deposits in neurons and glial cells, thus indicating a link between oxidative stress and tau phosphorylation in AGD. Hyperphosphorylated tau, in turn, co-localizes with p62/sequestosome 1 and ubiquitin, thus pointing to activation of protein aggregation and protein degradation pathways, respectively. Finally, AGs and tangles co-localize with mutant ubiquitin (UBB⁺¹) resulting from molecular misreading of mRNA, thus supporting proteasome function impairment and, therefore, impelling accumulation of hyperphosphorylated tau in AGs and tangles. The sequestration of active kinases in AGs and tangles is an additional local cause of tau hyperphosphorylation.

The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease

Pan, T., Kondo, S., Le, W., Jankovic, J. — 2008-01-10

The ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are the two most important mechanisms that normally repair or remove abnormal proteins. Alterations in the function of these systems to degrade misfolded and aggregated proteins are being increasingly recognized as playing a pivotal role in the pathogenesis of many neurodegenerative disorders such as Parkinson's disease. Dysfunction of the UPS has been already strongly implicated in the pathogenesis of this disease and, more recently, growing interest has been shown in identifying the role of ALP in neurodegeneration. Mutations of -synuclein and the increase of intracellular concentrations of non-mutant -synuclein have been associated with Parkinson's disease phenotype. The demonstration that -synuclein is degraded by both proteasome and autophagy indicates a possible linkage between the dysfunction of the UPS or ALP and the occurrence of this disorder. The fact that mutant -synucleins inhibit ALP functioning by tightly binding to the receptor on the lysosomal membrane for autophagy pathway further supports the assumption that impairment of the ALP may be related to the development of Parkinson's disease. In this review, we summarize the recent findings related to this topic and discuss the unique role of the ALP in this neurogenerative disorder and the putative therapeutic potential through ALP enhancement.

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

Fiorio, M., Tinazzi, M., Aglioti, S. M. — 2005-05-25