Brain - current issue

Clinical trials for the treatment of spinal cord injury: cervical and lumbar enlargements versus thoracic area

Rahimi-Movaghar, V. — 2009-06-24

Response: Clinical trials for the treatment of spinal cord injury: Cervical and lumbar enlargements versus thoracic area

Mackay-Sim, A. — 2009-06-24

Step training with severely damaged spinal cord

Wernig, A., Wernig, S. — 2009-06-24

Reply: Step training with severely damaged spinal cord

Phelps, P. E., Ramon-Cueto, A., Roy, R. R., Edgerton, V. R. — 2009-06-24

Change in grey matter volume cannot be assumed to be due to cognitive behavioural therapy

Kindlon, T. — 2009-06-24

Reply: Change in grey matter volume cannot be assumed to be due to cognitive behavioural therapy

de Lange, F. P., Bleijenberg, G., van der Meer, J. W. M., Hagoort, P., Toni, I. — 2009-06-24

Editorial

Compston, A. — 2009-06-24

Action recognition in the premotor cortex. By Vittorio Gallese, Luciano Fadiga, Leonardo Fogassi and Giacomo Rizzolatti. Brain 1996: 119; 593-609.

Compston, A. — 2009-06-24

Sodium channelopathy of peripheral nerve: tightening the genotype-phenotype relationship

Schorge, S., Kullmann, D. M. — 2009-06-24

The use of visual feedback, in particular mirror visual feedback, in restoring brain function

Ramachandran, V. S., Altschuler, E. L. — 2009-06-24

This article reviews the potential use of visual feedback, focusing on mirror visual feedback, introduced over 15 years ago, for the treatment of many chronic neurological disorders that have long been regarded as intractable such as phantom pain, hemiparesis from stroke and complex regional pain syndrome. Apart from its clinical importance, mirror visual feedback paves the way for a paradigm shift in the way we approach neurological disorders. Instead of resulting entirely from irreversible damage to specialized brain modules, some of them may arise from short-term functional shifts that are potentially reversible. If so, relatively simple therapies can be devised—of which mirror visual feedback is an example—to restore function.

Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation

2009-06-24

Inherited erythromelalgia (IEM), an autosomal dominant disorder characterized by severe burning pain in response to mild warmth, has been shown to be caused by gain-of-function mutations of sodium channel Na_v1.7 which is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Almost all physiologically characterized cases of IEM have been associated with onset in early childhood. Here, we report the voltage-clamp and current-clamp analysis of a new Na_v1.7 mutation, Q10R, in a patient with clinical onset of erythromelalgia in the second decade. We show that the mutation in this patient hyperpolarizes activation by only –5.3 mV, a smaller shift than seen with early-onset erythromelalgia mutations, but similar to that of I136V, another mutation that is linked to delayed-onset IEM. Using current-clamp, we show that the expression of Q10R induces hyperexcitability in DRG neurons, but produces an increase in excitability that is smaller than the change produced by I848T, an early-onset erythromelalgia mutation. Our analysis suggests a genotype–phenotype relationship at three levels (clinical, cellular and molecular/ion channel), with mutations that produce smaller effects on sodium channel activation being associated with a smaller degree of DRG neuron excitability and later onset of clinical signs.

The pattern and diagnostic criteria of sensory neuronopathy: a case-control study

2009-06-24

Acquired sensory neuronopathies encompass a group of paraneoplastic, dysimmune, toxic or idiopathic disorders characterized by degeneration of peripheral sensory neurons in dorsal root ganglia. As dorsal root ganglia cannot easily be explored, the clinical diagnosis of these disorders may be difficult. The question as to whether there exists a common clinical pattern of sensory neuronopathies, allowing the establishment of validated and easy-to-use diagnostic criteria, has not yet been addressed. In this study, logistic regression was used to construct diagnostic criteria on a retrospective study population of 78 patients with sensory neuronopathies and 56 with other sensory neuropathies. For this, sensory neuronopathy was provisionally considered as unambiguous in 44 patients with paraneoplastic disorder or cisplatin treatment and likely in 34 with a dysimmune or idiopathic setting who may theoretically have another form of neuropathy. To test the homogeneity of the sensory neuronopathy population, likely candidates were compared with unambiguous cases and then the whole population was compared with the other sensory neuropathies population. Criteria accuracy was checked on 37 prospective patients referred for diagnosis of sensory neuropathy. In the study population, sensory neuronopathy showed a common clinical and electrophysiological pattern that was independent of the underlying cause, including unusual forms with only patchy sensory loss, mild electrical motor nerve abnormalities and predominant small fibre or isolated lower limb involvement. Logistic regression allowed the construction of a set of criteria that gave fair results with the following combination: ataxia in the lower or upper limbs + asymmetrical distribution + sensory loss not restricted to the lower limbs + at least one sensory action potential absent or three sensory action potentials <30% of the lower limit of normal in the upper limbs + less than two nerves with abnormal motor nerve conduction study in the lower limbs.

PMP22 expression in dermal nerve myelin from patients with CMT1A

2009-06-24

Charcot-Marie-Tooth disease type 1A (CMT1A) is caused by a 1.4 Mb duplication on chromosome 17p11.2, which contains the peripheral myelin protein-22 (PMP22) gene. Increased levels of PMP22 in compact myelin of peripheral nerves have been demonstrated and presumed to cause the phenotype of CMT1A. The objective of the present study was to determine whether an extra copy of the PMP22 gene in CMT1A disrupts the normally coordinated expression of PMP22 protein in peripheral nerve myelin and to evaluate PMP22 over-expression in patients with CMT1A and determine whether levels of PMP22 are molecular markers of disease severity. PMP22 expression was measured by taking skin biopsies from patients with CMT1A (n = 20) and both healthy controls (n = 7) and patients with Hereditary Neuropathy with liability to Pressure Palsies (HNPP) (n = 6), in which patients have only a single copy of PMP22. Immunological electron microscopy was performed on the skin biopsies to quantify PMP22 expression in compact myelin. Similar biopsies were analysed by real time PCR to measure PMP22 mRNA levels. Results were also correlated with impairment in CMT1A, as measured by the validated CMT Neuropathy Score. Most, but not all patients with CMT1A, had elevated PMP22 levels in myelin compared with the controls. The levels of PMP22 in CMT1A were highly variable, but not in HNPP or the controls. However, there was no correlation between neurological disabilities and the level of over-expression of PMP22 protein or mRNA in patients with CMT1A. The extra copy of PMP22 in CMT1A results in disruption of the tightly regulated expression of PMP22. Thus, variability of PMP22 levels, rather than absolute level of PMP22, may play an important role in the pathogenesis of CMT1A.

Phenotypic spectrum of dynamin 2 mutations in Charcot-Marie-Tooth neuropathy

2009-06-24

Dominant intermediate Charcot-Marie-Tooth neuropathy type B is caused by mutations in dynamin 2. We studied the clinical, haematological, electrophysiological and sural nerve biopsy findings in 34 patients belonging to six unrelated dominant intermediate Charcot-Marie-Tooth neuropathy type B families in whom a dynamin 2 mutation had been identified: Gly358Arg (Spain); Asp551_Glu553del; Lys550fs (North America); Lys558del (Belgium); Lys558Glu (Australia, the Netherlands) and Thr855_Ile856del (Belgium). The Gly358Arg and Thr855_Ile856del mutations were novel, and in contrast to the other Charcot-Marie-Tooth-related mutations in dynamin 2, which are all located in the pleckstrin homology domain, they were situated in the middle domain and proline-rich domain of dynamin 2, respectively. We report the first disease-causing mutation in the proline-rich domain of dynamin 2. Patients with a dynamin 2 mutation presented with a classical Charcot-Marie-Tooth phenotype, which was mild to moderately severe since only 3% of the patients were wheelchair-bound. The mean age at onset was 16 years with a large variability ranging from 2 to 50 years. Interestingly, in the Australian and Belgian families, which carry two different mutations affecting the same amino acid (Lys558), Charcot-Marie-Tooth cosegregated with neutropaenia. In addition, early onset cataracts were observed in one of the Charcot-Marie-Tooth families. Our electrophysiological data indicate intermediate or axonal motor median nerve conduction velocities (NCV) ranging from 26 m/s to normal values in four families, and less pronounced reduction of motor median NCV (41–46 m/s) with normal amplitudes in two families. Sural nerve biopsy in a Dutch patient with Lys558Glu mutation showed diffuse loss of large myelinated fibres, presence of many clusters of regenerating myelinated axons and fibres with focal myelin thickenings—findings very similar to those previously reported in the Australian family. We conclude that dynamin 2 mutations should be screened in the autosomal dominant Charcot-Marie-Tooth neuropathy families with intermediate or axonal NCV, and in patients with a classical mild to moderately severe Charcot-Marie-Tooth phenotype, especially when Charcot-Marie-Tooth is associated with neutropaenia or cataracts.

Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with Dopa-responsive dystonia

2009-06-24

Dopa-responsive dystonia is a childhood-onset dystonic disorder, characterized by a dramatic response to low dose of l-Dopa. Dopa-responsive dystonia is mostly caused by autosomal dominant mutations in the GCH1 gene (GTP cyclohydrolase1) and more rarely by autosomal recessive mutations in the TH (tyrosine hydroxylase) or SPR (sepiapterin reductase) genes. In addition, mutations in the PARK2 gene (parkin) which causes autosomal recessive juvenile parkinsonism may present as Dopa-responsive dystonia. In order to evaluate the relative frequency of the mutations in these genes, but also in the genes involved in the biosynthesis and recycling of BH4, and to evaluate the associated clinical spectrum, we have studied a large series of index patients (n = 64) with Dopa-responsive dystonia, in whom dystonia improved by at least 50% after l-Dopa treatment. Fifty seven of these patients were classified as pure Dopa-responsive dystonia and seven as Dopa-responsive dystonia-plus syndromes. All patients were screened for point mutations and large rearrangements in the GCH1 gene, followed by sequencing of the TH and SPR genes, then PTS (pyruvoyl tetrahydropterin synthase), PCBD (pterin-4a-carbinolamine dehydratase), QDPR (dihydropteridin reductase) and PARK2 (parkin) genes. We identified 34 different heterozygous point mutations in 40 patients, and six different large deletions in seven patients in the GCH1 gene. Except for one patient with mental retardation and a large deletion of 2.3 Mb encompassing 10 genes, all patients had stereotyped clinical features, characterized by pure Dopa-responsive dystonia with onset in the lower limbs and an excellent response to low doses of l-Dopa. Dystonia started in the first decade of life in 40 patients (85%) and before the age of 1 year in one patient (2.2%). Three of the 17 negative GCH1 patients had mutations in the TH gene, two in the SPR gene and one in the PARK2 gene. No mutations in the three genes involved in the biosynthesis and recycling of BH4 were identified. The clinical presentations of patients with mutations in TH and SPR genes were strikingly more complex, characterized by mental retardation, oculogyric crises and parkinsonism and they were all classified as Dopa-responsive dystonia-plus syndromes. Patient with mutation in the PARK2 gene had Dopa-responsive dystonia with a good improvement with l-Dopa, similar to Dopa-responsive dystonia secondary to GCH1 mutations. Although the yield of mutations exceeds 80% in pure Dopa-responsive dystonia and Dopa-responsive dystonia-plus syndromes groups, the genes involved are clearly different: GCH1 in the former and TH and SPR in the later.

Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I

2009-06-24

In glutaric aciduria type I, an autosomal recessive disease of mitochondrial lysine, hydroxylysine and tryptophan catabolism, striatal lesions are characteristically induced by acute encephalopathic crises during a finite period of brain development (age 3–36 months). The frequency of striatal injury is significantly less in patients diagnosed as asymptomatic newborns by newborn screening. Most previous studies have focused on the onset and mechanism of striatal injury, whereas little is known about neuroradiological abnormalities in pre-symptomatically diagnosed patients and about dynamic changes of extrastriatal abnormalities. Thus, the major aim of the present retrospective study was to improve our understanding of striatal and extrastriatal abnormalities in affected individuals including those diagnosed by newborn screening. To this end, we systematically analysed magnetic resonance imagings (MRIs) in 38 patients with glutaric aciduria type I diagnosed before or after the manifestation of neurological symptoms. To identify brain regions that are susceptible to cerebral injury during acute encephalopathic crises, we compared the frequency of magnetic resonance abnormalities in patients with and without such crises. Major specific changes after encephalopathic crises were found in the putamen (P < 0.001), nucleus caudatus (P < 0.001), globus pallidus (P = 0.012) and ventricles (P = 0.001). Analysis of empirical cumulative distribution frequencies, however, demonstrated that isolated pallidal abnormalities did not significantly differ over time in both groups (P = 0.544) suggesting that isolated pallidal abnormalities are not induced by acute crises––in contrast to striatal abnormalities. The manifestation of motor disability was associated with signal abnormalities in putamen, caudate, pallidum and ventricles. In addition, we found a large number of extrastriatal abnormalities in patients with and without preceding encephalophatic crises. These abnormalities include widening of anterior temporal and sylvian CSF spaces, pseudocysts, signal changes of substantia nigra, nucleus dentatus, thalamus, tractus tegmentalis centralis and supratentorial white matter as well as signs of delayed maturation (myelination and gyral pattern). In contrast to the striatum, extrastriatal abnormalities were variable and could regress or even normalize with time. This includes widening of sylvian fissures, delayed maturation, pallidal signal changes and pseudocysts. Based on these results, we hypothesize that neuroradiological abnormalities and neurological symptoms in glutaric aciduria type I can be explained by overlaying episodes of cerebral alterations including maturational delay of the brain in utero, acute striatal injury during a vulnerable period in infancy and chronic progressive changes that may continue lifelong. This may have widespread consequences for the pathophysiological understanding of this disease, long-term outcomes and therapeutic considerations.

Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease

2009-06-24

Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12–12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant -synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5–6, and had McKeith's limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson's disease and suggest that to date, this is the most common genetic factor identified for the disease.

Gene expression profiling of substantia nigra dopamine neurons: further insights into Parkinson's disease pathology

2009-06-24

Parkinson's disease is caused by a progressive loss of the midbrain dopamine (DA) neurons in the substantia nigra pars compacta. Although the main cause of Parkinson's disease remains unknown, there is increasing evidence that it is a complex disorder caused by a combination of genetic and environmental factors, which affect key signalling pathways in substantia nigra DA neurons. Insights into pathogenesis of Parkinson's disease stem from in vitro and in vivo models and from postmortem analyses. Recent technological developments have added a new dimension to this research by determining gene expression profiles using high throughput microarray assays. However, many of the studies reported to date were based on whole midbrain dissections, which included cells other than DA neurons. Here, we have used laser microdissection to isolate single DA neurons from the substantia nigra pars compacta of controls and subjects with idiopathic Parkinson's disease matched for age and postmortem interval followed by microarrays to analyse gene expression profiling. Our data confirm a dysregulation of several functional groups of genes involved in the Parkinson's disease pathogenesis. In particular, we found prominent down-regulation of members of the PARK gene family and dysregulation of multiple genes associated with programmed cell death and survival. In addition, genes for neurotransmitter and ion channel receptors were also deregulated, supporting the view that alterations in electrical activity might influence DA neuron function. Our data provide a ‘molecular fingerprint identity’ of late–stage Parkinson's disease DA neurons that will advance our understanding of the molecular pathology of this disease.

Depletion of medullary serotonergic neurons in patients with multiple system atrophy who succumbed to sudden death

2009-06-24

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by prominent autonomic failure with ataxia and/or parkinsonism. The leading cause of death in MSA is sudden death. We have shown that the early development of autonomic failure is an independent risk factor for sudden death. The depletion of sympathetic preganglionic neurons in the spinal intermediolateral cell column (IML) and its afferent medullary catecholaminergic and serotonergic neurons has been proposed to be partly responsible for autonomic failure in MSA. In this study, we investigated whether the depletion of neurons in any of these autonomic neuron groups contributes to sudden death in MSA. Out of 52 autopsy-proven patients with MSA, we selected 12 individuals who had died within 3.5 years after disease onset to define the accurate levels of slices and identify early neuropathological changes of autonomic nuclei in MSA. Four patients succumbed to sudden death and eight patients died through established causes. Serial 10 µm sections were obtained from the 8th segment of the thoracic cord and the rostral medulla oblongata. Sections from the medulla oblongata were immunostained for thyrosine hydroxylase and tryptophan hydroxylase. The total cell number in the five sections was computed for comparison. Compared with the control, the MSA group showed a marked depletion of neurons in the IML (38.0 ± 7.1 versus 75.2 ± 7.6 cells, P < 0.001), thyrosine hydroxylase-immunoreactive neurons in the ventrolateral medulla (VLM) (17.4 ± 5.1 versus 72.8 ± 13.6 cells, P < 0.01) and tryptophan hydroxylase-immunoreactive neurons in the VLM (15.6 ± 9.2 versus 60.8 ± 17.0 cells, P < 0.01), nucleus raphe obscurus (19.3 ± 4.4 versus 75.3 ± 8.6 cells, P < 0.001), nucleus raphe pallidus (2.1 ± 2.7 versus 9.0 ± 3.4 cells, P < 0.03), and arcuate nucleus (0.4 ± 0.8 versus 2.3 ± 1.5 cells, P < 0.05). Moreover, in patients who succumbed to sudden death, when compared with patients who had established causes of death, we found a marked depletion of tryptophan hydroxylase-immunoreactive neurons in the VLM (7.3 ± 3.5 versus 21.8 ± 6.5 cells, P < 0.02) and nucleus raphe obscurus (15.0 ± 2.0 versus 22.5 ± 2.1 cells, P < 0.01). The results indicate that the spinal IML and medullary catecholaminergic and serotonergic systems are involved even in the early stages of MSA, and the dysfunction of the medullary serotonergic system regulating cardiovascular and respiratory systems could be responsible for sudden death in patients with MSA.

Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease

2009-06-24

It has been established for a long time that brain glucose metabolism is impaired in Alzheimer's disease. Recent studies have demonstrated that impaired brain glucose metabolism precedes the appearance of clinical symptoms, implying its active role in the development of Alzheimer's disease. However, the molecular mechanism by which this impairment contributes to the disease is not known. In this study, we demonstrated that protein O-GlcNAcylation, a common post-translational modification of nucleocytoplasmic proteins with β-N-acetyl-glucosamine and a process regulated by glucose metabolism, was markedly decreased in Alzheimer's disease cerebrum. More importantly, the decrease in O-GlcNAc correlated negatively with phosphorylation at most phosphorylation sites of tau protein, which is known to play a crucial role in the neurofibrillary degeneration of Alzheimer's disease. We also found that hyperphosphorylated tau contained 4-fold less O-GlcNAc than non-hyperphosphorylated tau, demonstrating for the first time an inverse relationship between O-GlcNAcylation and phosphorylation of tau in the human brain. Downregulation of O-GlcNAcylation by knockdown of O-GlcNAc transferase with small hairpin RNA led to increased phosphorylation of tau in HEK-293 cells. Inhibition of the hexosamine biosynthesis pathway in rat brain resulted in decreased O-GlcNAcylation and increased phosphorylation of tau, which resembled changes of O-GlcNAcylation and phosphorylation of tau in rodent brains with decreased glucose metabolism induced by fasting, but not those in rat brains when protein phosphatase 2A was inhibited. Comparison of tau phosphorylation patterns under various conditions suggests that abnormal tau hyperphosphorylation in Alzheimer's disease brain may result from downregulation of both O-GlcNAcylation and protein phosphatase 2A. These findings suggest that impaired brain glucose metabolism leads to abnormal hyperphosphorylation of tau and neurofibrillary degeneration via downregulation of tau O-GlcNAcylation in Alzheimer's disease. Thus, restoration of brain tau O-GlcNAcylation and protein phosphatase 2A activity may offer promising therapeutic targets for treating Alzheimer's disease.

The neural correlates of verbal short-term memory in Alzheimer's disease: an fMRI study

Peters, F., Collette, F., Degueldre, C., Sterpenich, V., Majerus, S., Salmon, E. — 2009-06-24

Although many studies have shown diminished performance in verbal short-term memory tasks in Alzheimer's disease, few studies have explored the neural correlates of impaired verbal short-term memory in Alzheimer's disease patients. In this fMRI study, we examined alterations in brain activation patterns during a verbal short-term memory recognition task, by differentiating encoding and retrieval phases. Sixteen mild Alzheimer's disease patients and 16 elderly controls were presented with lists of four words followed, after a few seconds, by a probe word. Participants had to judge whether the probe matched one of the items of the memory list. In both groups, the short-term memory task elicited a distributed fronto-parieto-temporal activation that encompassed bilateral inferior frontal, insular, supplementary motor, precentral and postcentral areas, consistent with previous studies of verbal short-term memory in young subjects. Most notably, Alzheimer's disease patients showed reduced activation in several regions during the encoding phase, including the bilateral middle frontal and the left inferior frontal gyri (associated with executive control processes) as well as the transverse temporal gyri (associated with phonological processing). During the recognition phase, we found decreased activation in the left supramarginal gyrus and the right middle frontal gyrus in Alzheimer's disease patients compared with healthy seniors, possibly related to deficits in manipulation and decision processes for phonological information. At the same time, Alzheimer's disease patients showed increased activation in several brain areas, including the left parahippocampus and hippocampus, suggesting that Alzheimer's disease patients may recruit alternative recognition mechanisms when performing a short-term memory task. Overall, our results indicate that Alzheimer's disease patients show differences in the functional networks underlying memory over short delays, mostly in brain areas known to support phonological processing or executive functioning.

Anterior thalamic lesions stop synaptic plasticity in retrosplenial cortex slices: expanding the pathology of diencephalic amnesia

2009-06-24

Recent, convergent evidence places the anterior thalamic nuclei at the heart of diencephalic amnesia. However, the reasons for the severe memory loss in diencephalic amnesia remain unknown. A potential clue comes from the dense, reciprocal connections between the anterior thalamic nuclei and retrosplenial cortex, another region vital for memory. We now report a loss of synaptic plasticity [long-term depression (LTD)] in rat retrosplenial cortex slices months following an anterior thalamic lesion. The loss of LTD was lamina-specific, occurring only in superficial layers of the cortex and was associated with a decrease in GABA_A-mediated inhibitory transmission. As retrosplenial cortex is itself vital for memory, this distal lesion effect will amplify the impact of anterior thalamic lesions. These findings not only provide novel insights into the functional pathology of diencephalic amnesia and have implications for the aetiology of the posterior cingulate hypoactivity in Alzheimer's disease, but also show how distal changes in plasticity could contribute to diaschisis.

Increased binding to 5-HT1A and 5-HT2A receptors is associated with large vessel infarction and relative preservation of cognition

2009-06-24

Vascular dementia accounts for ~15–20% of all dementias. In addition, a significant subset of people with Alzheimer's disease have concurrent cerebrovascular disease. Vascular dementia is caused by different cerebrovascular morphological abnormalities including large artery territory infarction (multi-infarct vascular dementia) and sub-cortical ischaemic vascular dementia. Despite this distinction, there is a lack of studies examining the neurochemistry of individual vascular dementia subtypes. Serotonin is believed to play an important role in cognition, and serotonin receptors may provide a novel target for future anti-dementia therapeutics. This study aimed to determine levels of two serotonin receptors in subtypes of vascular dementia and relate any changes to cognition. We have determined, using saturation radioligand binding, the binding parameters (affinity and maximal binding) of (³H)-WAY 100635 binding to 5-HT_1A receptors and (³H)-ketanserin binding to 5-HT_2A receptors in post-mortem tissue from the frontal and temporal cortices of patients with either multi-infarct vascular dementia, sub-cortical ischaemic vascular dementia, mixed Alzheimer's disease/vascular dementia or stroke no dementia (SND). 5-HT_1A and 5-HT_2A receptor binding was significantly increased in the temporal cortex of patients with either multi-infarct vascular dementia or SND, compared to age-matched controls. 5-HT_1A receptor maximal binding in the temporal cortex was also positively correlated with cognition as determined by Mini-Mental State Examination (MMSE) and Cambridge Assessment of Mental Health for the Elderly scores (CAMCOG). These results reveal an important distinction between the neurochemistry of multi-infarct vascular dementia/SND and sub-cortical ischaemic vascular dementia, suggesting that pharmacological manipulation of serotonin offers the possibility to develop novel therapies for stroke and multi-infarct vascular dementia patients. The results also highlight the importance of the cortical 5-HT_1A receptor in mediating cognition.

Cortical spreading ischaemia is a novel process involved in ischaemic damage in patients with aneurysmal subarachnoid haemorrhage

2009-06-24

The term cortical spreading depolarization (CSD) describes a wave of mass neuronal depolarization associated with net influx of cations and water. Clusters of prolonged CSDs were measured time-locked to progressive ischaemic damage in human cortex. CSD induces tone alterations in resistance vessels, causing either transient hyperperfusion (physiological haemodynamic response) in healthy tissue; or hypoperfusion [inverse haemodynamic response = cortical spreading ischaemia (CSI)] in tissue at risk for progressive damage, which has so far only been shown experimentally. Here, we performed a prospective, multicentre study in 13 patients with aneurysmal subarachnoid haemorrhage, using novel subdural opto-electrode technology for simultaneous laser-Doppler flowmetry (LDF) and direct current-electrocorticography, combined with measurements of tissue partial pressure of oxygen (ptiO₂). Regional cerebral blood flow and electrocorticography were simultaneously recorded in 417 CSDs. Isolated CSDs occurred in 12 patients and were associated with either physiological, absent or inverse haemodynamic responses. Whereas the physiological haemodynamic response caused tissue hyperoxia, the inverse response led to tissue hypoxia. Clusters of prolonged CSDs were measured in five patients in close proximity to structural brain damage as assessed by neuroimaging. Clusters were associated with CSD-induced spreading hypoperfusions, which were significantly longer in duration (up to 144 min) than those of isolated CSDs. Thus, oxygen depletion caused by the inverse haemodynamic response may contribute to the establishment of clusters of prolonged CSDs and lesion progression. Combined electrocorticography and perfusion monitoring also revealed a characteristic vascular signature that might be used for non-invasive detection of CSD. Low-frequency vascular fluctuations (LF-VF) (f < 0.1 Hz), detectable by functional imaging methods, are determined by the brain's resting neuronal activity. CSD provides a depolarization block of the resting activity, recorded electrophysiologically as spreading depression of high-frequency-electrocorticography activity. Accordingly, we observed a spreading suppression of LF-VF, which accompanied spreading depression of high-frequency-electrocorticography activity, independently of whether CSD was associated with a physiological, absent or inverse haemodynamic response. Spreading suppressions of LF-VF thus allow the differentiation of progressive ischaemia and repair phases in a fashion similar to that shown previously for spreading depressions of high-frequency-electrocorticography activity. In conclusion, it is suggested that (i) CSI is a novel human disease mechanism associated with lesion development and a potential target for therapeutic intervention in stroke; and that (ii) prolonged spreading suppressions of LF-VF are a novel ‘functional marker’ for progressive ischaemia.

Reduced medial temporal lobe functionality in stroke patients: a functional magnetic resonance imaging study

Snaphaan, L., Rijpkema, M., Uden, I. v., Fernandez, G., de Leeuw, F.-E. — 2009-06-24

Stroke is a leading cause of disability, not only because of motor limitations, but also because of the frequent occurrence of post-stroke cognitive impairment. This is illustrated by the fact that the risk of post-stroke dementia is reportedly higher than a recurrent stroke. The loss of subcortical and cortical functions in the post-stroke cognitive dysfunction spectrum is usually well explained by the size and location of the infarction. However, this does not apply for post-stroke memory dysfunction (especially episodic memory dysfunction), as there is almost never an infarction in the medial temporal lobe. Involvement of the medial temporal lobe in post-stroke memory dysfunction seems likely since this structure is essential for memory encoding and retrieval. For a proper episodic memory function, the medial temporal lobe depends on intact connections with virtually the whole brain. Disconnection from other brain areas due to the infarction could lead to a reduced medial temporal lobe function and the attendant reduced episodic memory function. We investigated medial temporal lobe functionality in 28 ‘first-ever’ stroke patients and 22 healthy controls with the aid of functional magnetic resonance imaging. Stroke patients with a reduced episodic memory function 6–8 weeks after infarction had reduced medial temporal lobe functionality. Post-stroke reduced medial temporal lobe functionality may be responsible for the frequent observation of impaired post-stroke episodic memory function. Insight into this mechanism could be helpful in identifying which stroke patients may be at increased risk for developing post-stroke dementia and those who could benefit from early cognitive rehabilitation.

Implicit representation and explicit detection of features in patients with hemispatial neglect

Van Vleet, T. M., Robertson, L. C. — 2009-06-24

Despite profound inattention to the side of space opposite a brain lesion in patients with unilateral neglect, priming studies demonstrate that undetected stimuli are capable of influencing subsequent behaviour. However, the nature of implicit processing of neglected stimuli is poorly understood. In the current study, we examined implicit processing in five patients with neglect using both visual search and priming methods. A psychophysical staircase method varying time of presentation was first used to establish a high (75%) and low (25%) detection probability for targets in both a feature and a conjunction search array. The arrays were then used in a priming task to examine how a difference in the level of overt detection of a feature or a conjunction presented in neglected space influenced subsequent discrimination speed to a single probe presented at fixation. The results showed that priming effects with feature primes were independent of their explicit detection rates (high versus low), but priming effects with conjunction primes reflected the pattern of explicit detection. These findings are discussed as they relate to availability versus accessibility of neglected stimuli.

Changes in cortical grey matter density associated with long-standing retinal visual field defects

2009-06-24

Retinal lesions caused by eye diseases such as glaucoma and age-related macular degeneration can, over time, eliminate stimulation of parts of the visual cortex. This could lead to degeneration of inactive cortical neuronal tissue, but this has not been established in humans. Here, we used magnetic resonance imaging to assess the effects of prolonged sensory deprivation in human visual cortex. High-resolution anatomical magnetic resonance images were obtained in subjects with foveal (age-related macular degeneration) and peripheral (glaucoma) retinal lesions as well as age-matched controls. Comparison of grey matter between patient and control groups revealed density reductions in the approximate retinal lesion projection zones in visual cortex. This indicates that long-term cortical deprivation, due to retinal lesions acquired later in life, is associated with retinotopic-specific neuronal degeneration of visual cortex. Such degeneration could interfere with therapeutic strategies such as the future application of artificial retinal implants to overcome lesion-induced visual impairment.

About the role of visual field defects in pure alexia

2009-06-24

Pure alexia is an acquired reading disorder characterized by a disproportionate prolongation of reading time as a function of word length. Although the vast majority of cases reported in the literature show a right-sided visual defect, little is known about the contribution of this low-level visual impairment to their reading difficulties. The present study was aimed at investigating this issue by comparing eye movement patterns during text reading in six patients with pure alexia with those of six patients with hemianopic dyslexia showing similar right-sided visual field defects. We found that the role of the field defect in the reading difficulties of pure alexics was highly deficit-specific. While the amplitude of rightward saccades during text reading seems largely determined by the restricted visual field, other visuo-motor impairments—particularly the pronounced increases in fixation frequency and viewing time as a function of word length—may have little to do with their visual field defect. In addition, subtracting the lesions of the hemianopic dyslexics from those found in pure alexics revealed the largest group differences in posterior parts of the left fusiform gyrus, occipito-temporal sulcus and inferior temporal gyrus. These regions included the coordinate assigned to the centre of the visual word form area in healthy adults, which provides further evidence for a relation between pure alexia and a damaged visual word form area. Finally, we propose a list of three criteria that may improve the differential diagnosis of pure alexia and allow appropriate therapy recommendations.

Neural processing of spoken words in specific language impairment and dyslexia

Helenius, P., Parviainen, T., Paetau, R., Salmelin, R. — 2009-06-24

Young adults with a history of specific language impairment (SLI) differ from reading-impaired (dyslexic) individuals in terms of limited vocabulary and poor verbal short-term memory. Phonological short-term memory has been shown to play a significant role in learning new words. We investigated the neural signatures of auditory word recognition and word repetition in young adults with SLI, dyslexia and normal language development using magnetoencephalography. The stimuli were 7-8 letter spoken real words and pseudo-words. They evoked a transient peak at 100 ms (N100m) followed by longer-lasting activation peaking around 400 ms (N400m) in the left and right superior temporal cortex. Both word repetition (first vs. immediately following second presentation) and lexicality (words vs. pseudowords) modulated the N400m response. An effect of lexicality was detected about 400 ms onwards as activation culminated for words but continued for pseudo-words. This effect was more pronounced in the left than right hemisphere in the control subjects. The left hemisphere lexicality effect was also present in the dyslexic adults, but it was non-significant in the subjects with SLI, possibly reflecting their limited vocabulary. The N400m activation between 200 and 700 ms was attenuated by the immediate repetition of words and pseudo-words in both hemispheres. In SLI adults the repetition effect evaluated at 200–400 ms was abnormally weak. This finding suggests impaired short-term maintenance of linguistic activation that underlies word recognition. Furthermore, the size of the repetition effect decreased from control subjects through dyslexics to SLIs, i.e. when advancing from milder to more severe language impairment. The unusually rapid decay of speech-evoked activation could have a detrimental role on vocabulary growth in children with SLI.

Enhanced activation of the left inferior frontal gyrus in deaf and dyslexic adults during rhyming

MacSweeney, M., Brammer, M. J., Waters, D., Goswami, U. — 2009-06-24

Hearing developmental dyslexics and profoundly deaf individuals both have difficulties processing the internal structure of words (phonological processing) and learning to read. In hearing non-impaired readers, the development of phonological representations depends on audition. In hearing dyslexics, many argue, auditory processes may be impaired. In congenitally profoundly deaf individuals, auditory speech processing is essentially absent. Two separate literatures have previously reported enhanced activation in the left inferior frontal gyrus in both deaf and dyslexic adults when contrasted with hearing non-dyslexics during reading or phonological tasks. Here, we used a rhyme judgement task to compare adults from these two special populations to a hearing non-dyslexic control group. All groups were matched on non-verbal intelligence quotient, reading age and rhyme performance. Picture stimuli were used since this requires participants to generate their own phonological representations, rather than have them partially provided via text. By testing well-matched groups of participants on the same task, we aimed to establish whether previous literatures reporting differences between individuals with and without phonological processing difficulties have identified the same regions of differential activation in these two distinct populations. The data indicate greater activation in the deaf and dyslexic groups than in the hearing non-dyslexic group across a large portion of the left inferior frontal gyrus. This includes the pars triangularis, extending superiorly into the middle frontal gyrus and posteriorly to include the pars opercularis, and the junction with the ventral precentral gyrus. Within the left inferior frontal gyrus, there was variability between the two groups with phonological processing difficulties. The superior posterior tip of the left pars opercularis, extending into the precentral gyrus, was activated to a greater extent by deaf than dyslexic participants, whereas the superior posterior portion of the pars triangularis extending into the ventral pars opercularis, was activated to a greater extent by dyslexic than deaf participants. Whether these regions play differing roles in compensating for poor phonological processing is not clear. However, we argue that our main finding of greater inferior frontal gyrus activation in both groups with phonological processing difficulties in contrast to controls suggests greater reliance on the articulatory component of speech during phonological processing when auditory processes are absent (deaf group) or impaired (dyslexic group). Thus, the brain appears to develop a similar solution to a processing problem that has different antecedents in these two populations.

Neural correlates of pragmatic language comprehension in autism spectrum disorders

2009-06-24

Difficulties with pragmatic aspects of communication are universal across individuals with autism spectrum disorders (ASDs). Here we focused on an aspect of pragmatic language comprehension that is relevant to social interaction in daily life: the integration of speaker characteristics inferred from the voice with the content of a message. Using functional magnetic resonance imaging (fMRI), we examined the neural correlates of the integration of voice-based inferences about the speaker's age, gender or social background, and sentence content in adults with ASD and matched control participants. Relative to the control group, the ASD group showed increased activation in right inferior frontal gyrus (RIFG; Brodmann area 47) for speaker-incongruent sentences compared to speaker-congruent sentences. Given that both groups performed behaviourally at a similar level on a debriefing interview outside the scanner, the increased activation in RIFG for the ASD group was interpreted as being compensatory in nature. It presumably reflects spill-over processing from the language dominant left hemisphere due to higher task demands faced by the participants with ASD when integrating speaker characteristics and the content of a spoken sentence. Furthermore, only the control group showed decreased activation for speaker-incongruent relative to speaker-congruent sentences in right ventral medial prefrontal cortex (vMPFC; Brodmann area 10), including right anterior cingulate cortex (ACC; Brodmann area 24/32). Since vMPFC is involved in self-referential processing related to judgments and inferences about self and others, the absence of such a modulation in vMPFC activation in the ASD group possibly points to atypical default self-referential mental activity in ASD. Our results show that in ASD compensatory mechanisms are necessary in implicit, low-level inferential processes in spoken language understanding. This indicates that pragmatic language problems in ASD are not restricted to high-level inferential processes, but encompass the most basic aspects of pragmatic language processing.

Hemispheric competence for auditory spatial representation

Spierer, L., Bellmann-Thiran, A., Maeder, P., Murray, M. M., Clarke, S. — 2009-06-24

Sound localization relies on the analysis of interaural time and intensity differences, as well as attenuation patterns by the outer ear. We investigated the relative contributions of interaural time and intensity difference cues to sound localization by testing 60 healthy subjects: 25 with focal left and 25 with focal right hemispheric brain damage. Group and single-case behavioural analyses, as well as anatomo-clinical correlations, confirmed that deficits were more frequent and much more severe after right than left hemispheric lesions and for the processing of interaural time than intensity difference cues. For spatial processing based on interaural time difference cues, different error types were evident in the individual data. Deficits in discriminating between neighbouring positions occurred in both hemispaces after focal right hemispheric brain damage, but were restricted to the contralesional hemispace after focal left hemispheric brain damage. Alloacusis (perceptual shifts across the midline) occurred only after focal right hemispheric brain damage and was associated with minor or severe deficits in position discrimination. During spatial processing based on interaural intensity cues, deficits were less severe in the right hemispheric brain damage than left hemispheric brain damage group and no alloacusis occurred. These results, matched to anatomical data, suggest the existence of a binaural sound localization system predominantly based on interaural time difference cues and primarily supported by the right hemisphere. More generally, our data suggest that two distinct mechanisms contribute to: (i) the precise computation of spatial coordinates allowing spatial comparison within the contralateral hemispace for the left hemisphere and the whole space for the right hemisphere; and (ii) the building up of global auditory spatial representations in right temporo-parietal cortices.

Evaluation of evoked potentials to dyadic tones after cochlear implantation

2009-06-24

Auditory evoked potentials are tools widely used to assess auditory cortex functions in clinical context. However, in cochlear implant users, electrophysiological measures are challenging due to implant-created artefacts in the EEG. Here, we used independent component analysis to reduce cochlear implant-related artefacts in event-related EEGs of cochlear implant users (n = 12), which allowed detailed spatio-temporal evaluation of auditory evoked potentials by means of dipole source analysis. The present study examined hemispheric asymmetries of auditory evoked potentials to musical sounds in cochlear implant users to evaluate the effect of this type of implantation on neuronal activity. In particular, implant users were presented with two dyadic tonal intervals in an active oddball design and in a passive listening condition. Principally, the results show that independent component analysis is an efficient approach that enables the study of neurophysiological mechanisms of restored auditory function in cochlear implant users. Moreover, our data indicate altered hemispheric asymmetries for dyadic tone processing in implant users compared with listeners with normal hearing (n = 12). We conclude that the evaluation of auditory evoked potentials are of major relevance to understanding auditory cortex function after cochlear implantation and could be of substantial clinical value by indicating the maturation/reorganization of the auditory system after implantation.

Encoding of human action in Broca's area

2009-06-24

Broca's area has been considered, for over a century, as the brain centre responsible for speech production. Modern neuroimaging and neuropsychological evidence have suggested a wider functional role is played by this area. In addition to the evidence that it is involved in syntactical analysis, mathematical calculation and music processing, it has recently been shown that Broca's area may play some role in language comprehension and, more generally, in understanding actions of other individuals. As shown by functional magnetic resonance imaging, Broca's area is one of the cortical areas activated by hand/mouth action observation and it has been proposed that it may form a crucial node of a human mirror-neuron system. If, on the one hand, neuroimaging studies use a correlational approach which cannot offer a final proof for such claims, available neuropsychological data fail to offer a conclusive demonstration for two main reasons: (i) they use tasks taxing both language and action systems; and (ii) they rarely consider the possibility that Broca's aphasics may also be affected by some form of apraxia. We administered a novel action comprehension test—with almost no linguistic requirements—on selected frontal aphasic patients lacking apraxic symptoms. Patients, as well as matched controls, were shown short movies of human actions or of physical events. Their task consisted of ordering, in a temporal sequence, four pictures taken from each movie and randomly presented on the computer screen. Patient's performance showed a specific dissociation in their ability to re-order pictures of human actions (impaired) with respect to physical events (spared). Our study provides a demonstration that frontal aphasics, not affected by apraxia, are specifically impaired in their capability to correctly encode observed human actions.

Another way to understand

Freund, H.-J. — 2009-06-24

Erratum

2009-06-24