Showing papers in "Brain in 2002"

Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes.

Abstract: Ten able adults with autism or Asperger syndrome and 10 normal volunteers were PET scanned while watching animated sequences. The animations depicted two triangles moving about on a screen in three different conditions: moving randomly, moving in a goal-directed fashion (chasing, fighting), and moving interactively with implied intentions (coaxing, tricking). The last condition frequently elicited descriptions in terms of mental states that viewers attributed to the triangles (mentalizing). The autism group gave fewer and less accurate descriptions of these latter animations, but equally accurate descriptions of the other animations compared with controls. While viewing animations that elicited mentalizing, in contrast to randomly moving shapes, the normal group showed increased activation in a previously identified mentalizing network (medial prefrontal cortex, superior temporal sulcus at the temporo-parietal junction and temporal poles). The autism group showed less activation than the normal group in all these regions. However, one additional region, extrastriate cortex, which was highly active when watching animations that elicited mentalizing, showed the same amount of increased activation in both groups. In the autism group this extrastriate region showed reduced functional connectivity with the superior temporal sulcus at the temporo-parietal junction, an area associated with the processing of biological motion as well as with mentalizing. This finding suggests a physiological cause for the mentalizing dysfunction in autism: a bottleneck in the interaction between higher order and lower order perceptual processes.

Pharmacological approach to the mechanisms of transcranial DC‐stimulation‐induced after‐effects of human motor cortex excitability

Abstract: Weak transcranial direct current stimulation (tDCS) induces persisting excitability changes in the human motor cortex. These plastic excitability changes are selectively controlled by the polarity, duration and current strength of stimulation. To reveal the underlying mechanisms of direct current (DC)-induced neuroplasticity, we combined tDCS of the motor cortex with the application of Na(+)-channel-blocking carbamazepine (CBZ) and the N-methyl-D-aspartate (NMDA)-receptor antagonist dextromethorphan (DMO). Monitored by transcranial magnetic stimulation (TMS), motor cortical excitability changes of up to 40% were achieved in the drug-free condition. Increase of cortical excitability could be selected by anodal stimulation, and decrease by cathodal stimulation. Both types of excitability change lasted several minutes after cessation of current stimulation. DMO suppressed the post-stimulation effects of both anodal and cathodal DC stimulation, strongly suggesting the involvement of NMDA receptors in both types of DC-induced neuroplasticity. In contrast, CBZ selectively eliminated anodal effects. Since CBZ stabilizes the membrane potential voltage-dependently, the results reveal that after-effects of anodal tDCS require a depolarization of membrane potentials. Similar to the induction of established types of short- or long-term neuroplasticity, a combination of glutamatergic and membrane mechanisms is necessary to induce the after-effects of tDCS. On the basis of these results, we suggest that polarity-driven alterations of resting membrane potentials represent the crucial mechanisms of the DC-induced after-effects, leading to both an alteration of spontaneous discharge rates and to a change in NMDA-receptor activation.

Language‐specific tuning of visual cortex? Functional properties of the Visual Word Form Area

Abstract: The first steps in the process of reading a printed word belong to the domain of visual object perception. They culminate in a representation of letter strings as an ordered set of abstract letter identities, a representation known as the Visual Word Form (VWF). Brain lesions in patients with pure alexia and functional imaging data suggest that the VWF is subtended by a restricted patch of left-hemispheric fusiform cortex, which is reproducibly activated during reading. In order to determine whether the operation of this Visual Word Form Area (VWFA) depends exclusively on the visual features of stimuli, or is influenced by language-dependent parameters, brain activations induced by words, consonant strings and chequerboards were compared in normal subjects using functional MRI (fMRI). Stimuli were presented in the left or right visual hemifield. The VWFA was identified in both a blocked-design experiment and an event-related experiment as a left-hemispheric inferotemporal area showing a stronger activation to alphabetic strings than to chequerboards, and invariant for the spatial location of stimuli. In both experiments, stronger activations of the VWFA to words than to strings of consonants were observed. Considering that the VWFA is equally activated by real words and by readable pseudowords, this result demonstrates that the VWFA is initially plastic and becomes attuned to the orthographic regularities that constrain letter combination during the acquisition of literacy. Additionally, the use of split-field stimulation shed some light on the cerebral bases of the classical right visual field (RVF) advantage in reading. A left occipital extrastriate area was found to be activated by RVF letter strings more than by chequerboards, while no symmetrical region was observed in the right hemisphere. Moreover, activations in the precuneus and the left thalamus were observed when subjects were reading RVF versus left visual field (LVF) words, and are likely to reflect the attentional component of the RVF advantage.

The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service

Abstract: We have reviewed the clinical and pathological diagnoses of 143 cases of parkinsonism seen by neurologists associated with the movement disorders service at The National Hospital for Neurology and Neurosurgery in London who came to neuropathological examination at the United Kingdom Parkinson's Disease Society Brain Research Centre, over a 10-year period between 1990 and the end of 1999. Seventy-three (47 male, 26 female) cases were diagnosed as having idiopathic Parkinson's disease (IPD) and 70 (42 male, 28 female) as having another parkinsonian syndrome. The positive predictive value of the clinical diagnosis for the whole group was 85.3%, with 122 cases correctly clinically diagnosed. The positive predictive value of the clinical diagnosis of IPD was extremely high, at 98.6% (72 out of 73), while for the other parkinsonian syndromes it was 71.4% (50 out of 70). The positive predictive values of a clinical diagnosis of multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) were 85.7 (30 out of 35) and 80% (16 out of 20), respectively. The sensitivity for IPD was 91.1%, due to seven false-negative cases, with 72 of the 79 pathologically established cases being diagnosed in life. For MSA, the sensitivity was 88.2% (30 out of 34), and for PSP it was 84.2% (16 out of 19). The diagnostic accuracy for IPD, MSA and PSP was higher than most previous prospective clinicopathological series and studies using the retrospective application of clinical diagnostic criteria. The seven false-negative cases of IPD suggest a broader clinical picture of disease than previously thought acceptable. This study implies that neurologists with particular expertise in the field of movement disorders may be using a method of pattern recognition for diagnosis which goes beyond that inherent in any formal set of diagnostic criteria.

A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica

Abstract: Devic's disease [neuromyelitis optica (NMO)] is an idiopathic inflammatory demyelinating disease of the CNS, characterized by attacks of optic neuritis and myelitis. The mechanisms that result in selective localization of inflammatory demyelinating lesions to the optic nerves and spinal cord are unknown. Serological and clinical evidence of B cell autoimmunity has been observed in a high proportion of patients with NMO. The purpose of this study was to investigate the importance of humoral mechanisms, including complement activation, in producing the necrotizing demyelination seen in the spinal cord and optic nerves. Eighty-two lesions were examined from nine autopsy cases of clinically confirmed Devic's disease. Demyelinating activity in the lesions was immunocytochemically classified as early active (21 lesions), late active (18 lesions), inactive (35 lesions) or remyelinating (eight lesions) by examining the antigenic profile of myelin degradation products within macrophages. The pathology of the lesions was analysed using a broad spectrum of immunological and neurobiological markers, and lesions were defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction and the immunopathological evidence of complement activation. The pathology was identical in all nine patients. Extensive demyelination was present across multiple spinal cord levels, associated with cavitation, necrosis and acute axonal pathology (spheroids), in both grey and white matter. There was a pronounced loss of oligodendrocytes within the lesions. The inflammatory infiltrates in active lesions were characterized by extensive macrophage infiltration associated with large numbers of perivascular granulocytes and eosinophils and rare CD3(+) and CD8(+) T cells. There was a pronounced perivascular deposition of immunoglobulins (mainly IgM) and complement C9neo antigen in active lesions associated with prominent vascular fibrosis and hyalinization in both active and inactive lesions. The extent of complement activation, eosinophilic infiltration and vascular fibrosis observed in the Devic NMO cases is more prominent compared with that in prototypic multiple sclerosis, and supports a role for humoral immunity in the pathogenesis of NMO. Based on this study, future therapeutic strategies designed to limit the deleterious effects of complement activation, eosinophil degranulation and neutrophil/macrophage/microglial activation are worthy of further investigation.

Neural correlates of self-reflection

Abstract: The capacity to reflect on one's sense of self is an important component of self-awareness. In this paper, we investigate some of the neurocognitive processes underlying reflection on the self using functional MRI. Eleven healthy volunteers were scanned with echoplanar imaging using the blood oxygen level-dependent contrast method. The task consisted of aurally delivered statements requiring a yes-no decision. In the experimental condition, participants responded to a variety of statements requiring knowledge of and reflection on their own abilities, traits and attitudes (e.g. 'I forget important things', 'I'm a good friend', 'I have a quick temper'). In the control condition, participants responded to statements requiring a basic level of semantic knowledge (e.g. 'Ten seconds is more than a minute', 'You need water to live'). The latter condition was intended to control for auditory comprehension, attentional demands, decision-making, the motoric response, and any common retrieval processes. Individual analyses revealed consistent anterior medial prefrontal and posterior cingulate activation for all participants. The overall activity for the group, using a random-effects model, occurred in anterior medial prefrontal cortex (t = 13.0, corrected P = 0.05; x, y, z, 0, 54, 8, respectively) and the posterior cingulate (t = 14.7, P = 0.02; x, y, z, -2, -62, 32, respectively; 967 voxel extent). These data are consistent with lesion studies of impaired awareness, and suggest that the medial prefrontal and posterior cingulate cortex are part of a neural system subserving self-reflective thought.

Imaging how attention modulates pain in humans using functional MRI.

Abstract: Current clinical and experimental literature strongly supports the phenomenon of reduced pain perception whilst attention is distracted away from noxious stimuli. This study used functional MRI to elucidate the underlying neural systems and mechanisms involved. An analogue of the Stroop task, the counting Stroop, was used as a cognitive distraction task whilst subjects received intermittent painful thermal stimuli. Pain intensity scores were significantly reduced when subjects took part in the more cognitively demanding interference task of the counting Stroop than in the less demanding neutral task. When subjects were distracted during painful stimulation, brain areas associated with the affective division of the anterior cingulate cortex (ACC) and orbitofrontal regions showed increased activation. In contrast, many areas of the pain matrix (i.e. thalamus, insula, cognitive division of the ACC) displayed reduced activation, supporting the behavioural results of reduced pain perception.

Decision-making processes following damage to the prefrontal cortex

Abstract: Recent work has suggested an association between the orbitofrontal cortex in humans and practical decision making. The aim of this study was to investigate the profile of cognitive deficits, with particular emphasis on decision‐making processes, following damage to different sectors of the human prefrontal cortex. Patients with discrete orbitofrontal (OBF) lesions, dorsolateral (DL) lesions, dorsomedial (DM) lesions and large frontal lesions (Large) were compared with matched controls on three different decision‐making tasks: the Iowa Gambling Task and two recently developed tasks that attempt to fractionate some of the cognitive components of the Iowa task. A comprehensive battery including the assessment of recognition memory, working memory, planning ability and attentional set‐shifting was also administered. Whilst combined frontal patients were impaired on several of the tasks employed, distinct profiles emerged for each patient group. In contrast to previous data, patients with focal OBF lesions performed at control levels on the three decision‐making tasks (and the executive tasks), but showed some evidence of prolonged deliberation. DL patients showed pronounced impairment on working memory, planning, attentional shifting and the Iowa Gambling Task. DM patients were impaired at the Iowa Gambling Task and also at planning. The Large group displayed diffuse impairment, but were the only group to exhibit risky decision making. Methodological differences from previous studies of OBF patient groups are discussed, with particular attention to lesion laterality, lesion size and psychiatric presentation. Ventral and dorsal aspects of prefrontal cortex must interact in the maintenance of rational and ‘non‐risky’ decision making. Received April 11, 2001. Revised August 16, 2001. Second revision October 19, 2001. Accepted October 22, 2001

Theory of mind in patients with frontal variant frontotemporal dementia and Alzheimer's disease: theoretical and practical implications

Abstract: A key aspect of social cognition is the ability to infer other people's mental states, thoughts and feelings; referred to as 'theory of mind' (ToM). We tested the hypothesis that the changes in personality and behaviour seen in frontal variant frontotemporal dementia (fvFTD) may reflect impairment in this cognitive domain. Tests of ToM, executive and general neuropsychological ability were given to 19 fvFTD patients, a comparison group of Alzheimer's disease patients (n = 12) and matched healthy controls (n = 16). Neuropsychiatric assessment was undertaken using the Neuropsychiatric Inventory (NPI). Patients with fvFTD were impaired on all tests of ToM (first-order false belief; second-order false belief; faux pas detection; and Reading the Mind in the Eyes), but had no difficulty with control questions designed to test general comprehension and memory. By contrast, the Alzheimer's disease group failed only one ToM task (second-order false belief), which places heavy demands on working memory. Performance on the faux pas test revealed a double dissociation, with the fvFTD group showing deficits on ToM-based questions and the Alzheimer's disease group failing memory-based questions only. Rank order of the fvFTD patients according to the magnitude of impairment on tests of ToM and their degree of frontal atrophy showed a striking concordance between ToM performances and ventromedial frontal damage. There was a significant correlation between the NPI score and more sophisticated tests of ToM in the fvFTD group. This study supports the hypothesis that patients with fvFTD, but not those with Alzheimer's disease, are impaired on tests of ToM, and may explain some of the abnormalities in interpersonal behaviour that characterize fvFTD.

Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time.

Abstract: Multiple sclerosis is characterized morphologically by the key features demyelination, inflammation, gliosis and axonal damage. In recent years, it has become more evident that axonal damage is the major morphological substrate of permanent clinical disability. In our study, we investigated the occurrence of acute axonal damage determined by immunocytochemistry for amyloid precursor protein (APP) which is produced in neurones and accumulates at sites of recent axon transection or damage. The numbers of APP-positive axons in multiple sclerosis lesions were correlated with the disease duration and course. Most APP-positive axons were detected within the first year after disease onset, but acute axonal damage was also detected to a minor degree in lesions of patients with a disease duration of 10 years and more. This effect was not due to the lack of active demyelinating lesions in the chronic disease stage. Late remyelinated lesions (so-called shadow plaques) did not show signs of axon destruction. The number of inflammatory cells showed a decrease over time similar to that of the number of APP-positive axons. There was a significant correlation between the extent of axon damage and the numbers of CD8-positive cytotoxic T cells and macrophages/microglia. Our results indicate that a putative axon-protective treatment should start as early as possible and include strategies preventing T cell/macrophage-mediated axon destruction and leading to remyelination of axons.

Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson's disease.

Abstract: Local field potentials and pairs of neurones in the subthalamic nucleus (STN) of patients with Parkinson's disease show high-frequency oscillations (HFOs) at 15-30 Hz. This study explores how these HFOs are modulated by voluntary movements and by dopaminergic medication. We examined 15 patients undergoing implantation of bilateral deep brain stimulating electrodes using microelectrode recordings of pairs of STN neurones (eight patients) and macroelectrode recordings of local field potentials from the STN (14 patients). Synchronized HFOs between STN neurones were observed in 28 out of 37 pairs in five patients who had tremor in the operating room and none of 45 pairs in three patients who did not. In two of the three non-tremulous patients, HFOs in the frequency spectra of local field potentials were detected but were weaker than in those patients with tremor. Active movement suppressed synchronized HFOs in three out of five pairs of neurones, independent of changes in firing rate. HFOs observed in the local field potentials in nine out of 14 patients were reduced with voluntary movement in six of the eight patients tested. Dopaminergic medication decreased the incidence of synchronized HFOs in STN neurone pairs, reduced HFO synchrony in a pair of tremor cells concurrent with a reduction in firing rate and limb tremor, and decreased HFOs of local field potentials in the STN. These results demonstrate that HFO synchronization in the STN is reduced by voluntary movements and by exogenous dopaminergic medication. A mechanism for neuronal oscillatory synchronization in basal ganglia is proposed. It is suggested that the firing of STN neurones can be synchronized by 15-30 Hz cortical beta oscillatory activity, particularly when dopamine deficiency results in a higher background firing rate of STN neurones, and that this synchronization contributes to parkinsonian pathophysiology.

Peripheral neuropathies and anti-glycolipid antibodies.

Abstract: This review charts the progress of anti-glycolipid antibodies in neuropathy, from their original discovery 20 years ago in immunoglobulin M paraproteinaemic neuropathy through to current discoveries mapping their relationship to subtypes of Guillain-Barre syndrome. Antibodies to >20 different glycolipids have now been associated with a wide range of clinically identifiable acute and chronic neuropathy syndromes. Particular progress has been achieved in understanding the link between acute motor axonal neuropathy and antibodies to GM1, GD1a, GM1b and GalNAc-GD1a, and between the cranial, bulbar and sensory variants of GBS and antibodies to the disialylated gangliosides GQ1b, GT1a, GD1b and GD3. In addition to clinical and serological studies, the origins and measurement of anti-glycolipid antibodies and their relationships to similar carbohydrate structures on infectious organisms, particularly Campylobacter jejuni, are discussed in the context of a molecular mimicry hypothesis. The structure and nomenclature of relevant glycolipids are outlined, along with information on their localization in nerve, and the influence this has on clinical phenotypes. Major advances have been made in animal modelling of anti-glycolipid antibody-associated diseases, both in vitro and in vivo. This has advanced our understanding of the role of anti-GQ1b antibodies in Miller Fisher syndrome with particular respect to the motor nerve terminal as a potential site of injury, and led to the creation of rabbit models of anti-GD1b and anti-GM1 antibody-mediated sensory and motor neuropathy, respectively. With such information in place, it will now be possible to determine the precise mechanisms by which antibodies injure the different compartments of peripheral nerve and establish how a range of immunomodulating therapies, including current treatments, exert their therapeutic effects. Despite these very significant advances, considerable gaps in our knowledge persist, and it is likely that other pathogenic pathways operate in inflammatory neuropathy that are unrelated to glycolipid antibodies, although these are outside the scope of this review.

Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance

Abstract: MRI methods are widely used to follow the pathological evolution of multiple sclerosis in life and its modification by treatment. To date, measures of the number and volume of macroscopically visible lesions have been studied most often. These MRI outcomes have demonstrated clear treatment effects but without a commensurate clinical benefit, suggesting that there are other aspects of multiple sclerosis pathology that warrant investigation. In this context, there has been considerable interest in measuring tissue loss (atrophy) as a more global marker of the adverse outcome of multiple sclerosis pathology, whether it arises in macroscopic lesions or in the normal appearing tissues. An International Workshop recently considered the measurement of atrophy in multiple sclerosis and provided the basis for this review. Brain white matter bulk consists predominantly of axons (46%) followed by myelin (24%), and progressive atrophy implies loss of these structures, especially axons, although variable effects on tissue volumes may also arise from glial cell proliferation or loss, gliosis, inflammation and oedema. Significant correlations found between brain volume and other putative MR neuronal markers also indicate that atrophy reflects axonal loss. Numerous methods are available for the measurement of global and regional brain volumes and upper cervical cord cross-sectional area that are highly reproducible and sensitive to changes within 6-12 months. In general, 3D-T(1)-weighted acquisitions and largely automated segmentation approaches are optimal. Whereas normalized volumes are desirable for cross-sectional studies, absolute volume measures are adequate for serial investigation. Atrophy is seen at all clinical stages of multiple sclerosis, developing gradually following the appearance of inflammatory lesions. This probably reflects both inflammation-induced axonal loss followed by Wallerian degeneration and post-inflammatory neurodegeneration that may be partly due to failure of remyelination. One component of atrophy appears to be independent of focal lesions. Existing immunomodulatory therapies have had limited effects on progressive atrophy, concordant with their modest effects on progressive disability. Atrophy provides a sensitive measure of the neurodegenerative component of multiple sclerosis and should be measured in trials evaluating potential anti-inflammatory, remyelinating or neuroprotective therapies.

Focal cortical dysplasia: neuropathological subtypes, EEG, neuroimaging and surgical outcome.

Abstract: Since the original description by Taylor, the term focal cortical dysplasia has been used to refer to a wide range of alterations of the cortical mantle. More recently, these conditions have been described from neuroimaging, neuropathological and genetic standpoints, generating several classifications. It is widely recognized that these classifications are unsatisfactory. We propose a simplified classification of focal cortical dysplasias based on easily recognized neuropathological characteristics. We retrospectively re-examined histological sections of cortex from 52 of 224 (23%) patients operated on for drug-resistant partial epilepsy in which cortical dysplasia was present but not associated with other brain pathologies except hippocampal sclerosis. Three subgroups were identified: (i) architectural dysplasia (31 patients) characterized by abnormal cortical lamination and ectopic neurones in white matter; (ii) cytoarchitectural dysplasia (six patients) characterized by giant neurofilament-enriched neurones in addition to altered cortical lamination; and (iii) Taylor-type cortical dysplasia (15 patients) with giant dysmorphic neurones and balloon cells (all but two patients) associated with cortical laminar disruption. The patients with architectural dysplasia had lower seizure frequency than those with cytoarchitectural and Taylor-type dysplasia, and the epileptogenic zone was mainly in the temporal lobe. In patients with Taylor-type dysplasia, the epileptogenic zone was mainly extratemporal, and interictal stereo-EEG was distinctive. MRI was unrevealing in 34% of patients, but distinctive signal alterations characterized most patients with Taylor-type dysplasia, while focal hypoplasia with MRI abnormalities was found in architectural dysplasia. Patients with Taylor-type dysplasia had the best outcome, with 75% seizure-free (Engel class Ia) after at least a year of follow-up compared with 50% of cytoarchitectural dysplasia and 43% of architectural dysplasia patients seizure-free. This three-category classification is based on easily recognized histopathological characteristics and avoids complicated terminology, while the distinctive ensemble of other characteristics defines clinically homogeneous groups.

Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study

Abstract: Only recently have neuroimaging studies moved away from describing regions activated by noxious stimuli and started to disentangle subprocesses within the nociceptive system. One approach to characterizing the role of individual regions is to record brain responses evoked by different stimulus intensities. We used such a parametric single-trial functional MRI design in combination with a thulium:yttrium-aluminium-granate infrared laser and investigated pain, stimulus intensity and stimulus awareness (i.e. pain-unrelated) responses in nine healthy volunteers. Four stimulus intensities, ranging from warm to painful (300-600 mJ), were applied in a randomized order and rated by the subjects on a five-point scale (P0-4). Regions in the dorsolateral prefrontal cortex and the intraparietal sulcus differentiated between P0 (not perceived) and P1 but exhibited no further signal increase with P2, and were related to stimulus perception and subsequent cognitive processing. Signal changes in the primary somatosensory cortex discriminated between non-painful trials (P0 and P1), linking this region to basic sensory processing. Pain-related regions in the secondary somatosensory cortex and insular cortex showed a response that did not distinguish between innocuous trials (P0 and P1) but showed a positive linear relationship with signal changes for painful trials (P2-4). This was also true for the amygdala, with the exception that, in P0 trials in which the stimulus was not perceived (i.e. 'uncertain' trials), the evoked signal changes were as great as in P3 trials, indicating that the amygdala is involved in coding 'uncertainty', as has been suggested previously in relation to classical conditioning.

Hypertension and cerebral white matter lesions in a prospective cohort study

Abstract: White matter lesions are frequently found on cerebral MRI scans of elderly people and are thought to be important in the pathogenesis of dementia. Hypertension has been associated with the presence of white matter lesions but this has been investigated almost exclusively in cross-sectional studies. We studied prospectively the association of these lesions with the duration and treatment of hypertension. We randomly sampled 1077 subjects aged between 60 and 90 years from two prospective population-based studies. One-half of the study subjects had their blood pressure measured between 1975 and 1978 and the other half between 1990 and 1993. All subjects underwent 1.5 T MRI scanning; white matter lesions in the subcortical and periventricular regions were rated separately. Subjects with hypertension had increased rates of both types of white matter lesion. Duration of hypertension was associated with both periventricular and subcortical white matter lesions. This relationship was influenced strongly by age. For participants with >20 years of hypertension and aged between 60 and 70 years at the time of follow-up, the relative risks for subcortical and periventricular white matter lesions were 24.3 [95% confidence interval (CI) 5.1-114.8] and 15.8 (95% CI 3.4-73.5), respectively, compared with normotensive subjects. Subjects with successfully treated hypertension had only moderately increased rates of subcortical white matter lesions and periventricular white matter lesions (relative risk 3.3, 95% CI 1.3-8.4 and 2.6, 95% CI 1.0-6.8, respectively) compared with normotensive subjects. For poorly controlled hypertensives, these relative risks were 8.4 (95% CI 3.1-22.6) and 5.8 (95% CI 2.1-16.0), respectively. In conclusion, we found a relationship between long-standing hypertension and the presence of white matter lesions. Our findings are consistent with the view that effective treatment may reduce the rates of both types of white matter lesion. Adequate treatment of hypertension may therefore prevent white matter lesions and the associated cognitive decline.

Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe.

Abstract: Consensus opinion characterizes dementia with Lewy bodies (DLB) as a progressive dementing illness, with significant fluctuations in cognition, visual hallucinations and/or parkinsonism. When parkinsonism is an early dominant feature, consensus opinion recommends that dementia within the first year is necessary for a diagnosis of DLB. If dementia occurs later, a diagnosis of Parkinson's disease with dementia (PDD) is recommended. While many previous studies have correlated the neuropathology in DLB with dementia and parkinsonism, few have analysed the relationship between fluctuating cognition and/or well-formed visual hallucinations and the underlying neuropathology in DLB and PDD. The aim of the present study was to determine any relationship between these less-studied core clinical features of DLB, and the distribution and density of cortical Lewy bodies (LB). The brains of 63 cases with LB were obtained over 6 years following population-based studies of dementia and parkinsonian syndromes. Annual, internationally standardized, clinical assessment batteries were reviewed to determine the presence and onset of the core clinical features of DLB. The maximal density of LB, plaques and tangles in the amygdala, parahippocampal, anterior cingulate, superior frontal, inferior temporal, inferior parietal and visual cortices were determined. Current clinicopathological diagnostic criteria were used to classify cases into DLB (n = 29), PDD (n = 18) or parkinsonism without dementia (n = 16) groups. Predictive statistics were used to ascertain whether fluctuating cognition or visual hallucinations predicted the clinicopathological group. Analysis of variance and regressions were used to identify any significant relationship(s) between the presence and severity of neuropathological and clinical features. Cognitive fluctuations and/or visual hallucinations were not good predictors of DLB in pathologically proven patients, although the absence of these features early in the disease course was highly predictive of PDD. Cases with DLB had higher LB densities in the inferior temporal cortex than cases with PDD. There was no association across groups between any neuropathological variable and the presence or absence of fluctuating cognition. However, there was a striking association between the distribution of temporal lobe LB and well-formed visual hallucinations. Cases with well-formed visual hallucinations had high densities of LB in the amygdala and parahippocampus, with early hallucinations relating to higher densities in parahippocampal and inferior temporal cortices. These temporal regions have previously been associated with visual hallucinations in other disorders. Thus, our results suggest that the distribution of temporal lobe LB is more related to the presence and duration of visual hallucinations in cases with LB than to the presence, severity or duration of dementia.

Correlation between motor improvements and altered fMRI activity after rehabilitative therapy

Abstract: Motor rehabilitation therapy is commonly employed after strokes, but outcomes are variable and there is little specific information about the changes in brain activity that are associated with improved function. We performed serial functional MRI (fMRI) on a group of seven patients receiving a form of rehabilitation therapy after stroke in order to characterize functional changes in the brain that correlate with behavioural improvements. Patients were scanned while performing a hand flexion-extension movement twice before and twice after a two-week home-based therapy programme combining restraint of the unaffected limb with progressive exercises for the affected limb. As expected, the extent of improvement in hand function after therapy varied between patients. Therapy-related improvements in hand function correlated with increases in fMRI activity in the premotor cortex and secondary somatosensory cortex contralateral to the affected hand, and in superior posterior regions of the cerebellar hemispheres bilaterally (Crus I and lobule VI). fMRI offers a promising, objective approach for specifically identifying changes in brain activity potentially responsible for rehabilitation-mediated recovery of function after stroke. Our results suggest that activity changes in sensorimotor regions are associated with successful motor rehabilitation.

Movement-related changes in synchronization in the human basal ganglia.

Abstract: There is a wealth of data suggesting that behavioural events are reflected in the basal ganglia through phasic changes in the discharge of individual neurones. Here we investigate whether events are also reflected in momentary changes in the degree of synchronization between neuronal elements. We simultaneously recorded local potentials (LPs) from the subthalamic nucleus (STN) and/or ipsilateral globus pallidus interna (GPi) or scalp EEG during voluntary movements of a hand-held joystick in six awake patients following neurosurgery for Parkinson's disease. Without medication the power within the STN and the coherence between the STN and the GPi were dominated by activity with a frequency of <30 Hz. This coupling was attenuated by movement. In the presence of exogenous dopaminergic stimulation, power within the STN and coherence between the STN and the GPi was dominated by activity at 70-85 Hz, which increased with movement. The movement-related changes in coherence between the STN and EEG showed a similar pattern of pharmacological dependence, as seen subcortically. Movement-related frequency-specific changes in synchronization occur in the basal ganglia and extend to involve subcortico-cortical motor loops. The dynamic organization of activities in the frequency domain might provide a means for temporal co-ordination within and across different processing streams in the basal ganglia. This organization is critically dependent on the level of dopaminergic activity.

Analysis of fMRI and finger tracking training in subjects with chronic stroke

Abstract: Hand movement recovery and cortical reorganization were studied in 10 subjects with chronic stroke using functional MRI (fMRI) before and after training with an intensive finger movement tracking programme. Subjects were assigned randomly to a treatment or control group. The treatment group received 18-20 sessions of finger tracking training using target waveforms under variable conditions. The control group crossed over to receive the same treatment after the control period. For comparison with a healthy population, nine well elderly females were also studied; however, the well elderly controls did not cross over after the control period. The dependent variables consisted of a Box and Block score to measure prehensile ability (subjects with stroke only), a tracking accuracy score and quantification of active cortical areas using fMRI. For the tracking tests, the subjects tracked a sine wave target on a computer screen with extension and flexion movements of the paretic index finger. Functional brain images were collected from the frontal and parietal lobes of the subject with a 4 tesla magnet. Areas of interest included the sensorimotor cortex (SMC), primary motor area (M1), primary sensory area (S1), premotor cortex (PMC) and supplementary motor area (SMA). Comparison between all subjects with stroke and all well elderly subjects at pre-test was analysed with two-sample t-tests. Change from pre-test to post-test within subjects was analysed with paired t-tests. Statistical significance was set at P < 0.05. Stroke treatment subjects demonstrated significant improvement in tracking accuracy, whereas stroke control subjects did not until after crossover treatment. At pre-test, the cortical activation in the subjects with stroke was predominantly ipsilateral to the performing hand, whereas in the well elderly subjects it was contralateral. Activation for the stroke treatment group following training switched to contralateral in SMC, M1, S1 and PMC. The stroke control group's activation remained ipsilateral after the control period, but switched to contralateral after crossover to receive treatment. All well elderly subjects maintained predominantly contralateral activation throughout. Transfer of skill to functional activity was shown in significantly improved Box and Block scores for the stroke treatment group, with no such improvement in the stroke control group until after crossover. We concluded that individuals with chronic stroke receiving intensive tracking training showed improved tracking accuracy and grasp and release function, and that these improvements were accompanied by brain reorganization.

Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients.

Abstract: We investigated the disease progression and survival in 230 Japanese patients with multiple system atrophy (MSA; 131 men, 99 women; 208 probable MSA, 22 definite; mean age at onset, 55.4 years). Cerebellar dysfunction (multiple system atrophy-cerebellar; MSA-C) predominated in 155 patients, and parkinsonism (multiple system atrophy-parkinsonian; MSA-P) in 75. The median time from initial symptom to combined motor and autonomic dysfunction was 2 years (range 1-10). Median intervals from onset to aid-requiring walking, confinement to a wheelchair, a bedridden state and death were 3, 5, 8 and 9 years, respectively. Patients manifesting combined motor and autonomic involvement within 3 years of onset had a significantly increased risk of not only developing advanced disease stage but also shorter survival (P < 0.01). MSA-P patients had more rapid functional deterioration than MSA-C patients (aid-requiring walking, P = 0.03; confinement to a wheelchair, P < 0.01; bedridden state, P < 0.01), but showed similar survival. Onset in older individuals showed increased risk of confinement to a wheelchair (P < 0.05), bedridden state (P = 0.03) and death (P < 0.01). Patients initially complaining of motor symptoms had accelerated risk of aid-requiring walking (P < 0.01) and confinement to a wheelchair (P < 0.01) compared with those initially complaining of autonomic symptoms, while the time until confinement to a bedridden state and survival were no worse. Gender was not associated with differences in worsening of function or survival. On MRI, a hyperintense rim at the lateral edge of the dorsolateral putamen was seen in 34.5% of cases, and a 'hot cross bun' sign in the pontine basis (PB) in 63.3%. These putaminal and pontine abnormalities became more prominent as MSA-P and MSA-C features advanced. The atrophy of the cerebellar vermis and PB showed a significant correlation particularly with the interval following the appearance of cerebellar symptoms in MSA-C (r = 0.71, P < 0.01, r = 0.76 and P < 0.01, respectively), but the relationship between atrophy and functional status was highly variable among the individuals, suggesting that other factors influenced the functional deterioration. Atrophy of the corpus callosum was seen in a subpopulation of MSA, suggesting hemispheric involvement in a subgroup of MSA patients. The present study suggested that many factors are involved in the progression of MSA but, most importantly, the interval from initial symptom to combined motor and autonomic dysfunction can predict functional deterioration and survival in MSA.

Intraoperative mapping of the subcortical language pathways using direct stimulations. An anatomo-functional study.

Abstract: Functional neuroimaging has improved pre-planning of surgery in eloquent cortical areas, but remains unable to map white matter. Thus, tumour resection in functional subcortical regions still presents a high risk of sequelae. The authors successfully used intraoperative electrical stimulations to perform subcortical language pathway mapping in order to avoid postoperative definitive deficit, and correlated these functional findings with the anatomical location of the eloquent bundles detected using postoperative MRI. At the same time, this also improved knowledge of fibre connectivity. Thirty patients harbouring a cortico-subcortical low-grade glioma in the left dominant hemisphere were operated on whilst awake using intraoperative electrical functional mapping during surgical resection. Language cortical sites and subcortical pathways were clearly identified and preserved in the 30 cases. The anatomo-functional correlations between data obtained using intraoperative subcortical mapping and postoperative MRI revealed the existence in all patients of common pathways which seem essential to language. This was shown by inducing reproducible speech disturbances during stimulations as follows: the subcallosal fasciculus (initiation disorders), the periventricular white matter (dysarthria), the arcuate fasciculus and the insular connections (anomia). Clinically, all patients except three presented a transient postoperative dysphasia, which resolved within 3 months. On control MRI, 14 resections were total and 16 subtotal due to infiltration of functional bundles described above. It is recommended that the combination of the techniques as described could prove ideal for future non-invasive reliable subcortical mapping both in healthy volunteers and in patients harbouring a (cortico)subcortical lesion in order to optimize surgical pre-planning.

Dopamine-dependent changes in the functional connectivity between basal ganglia and cerebral cortex in humans

Abstract: We test the hypothesis that interaction between the human basal ganglia and cerebral cortex involves activity in multiple functional circuits characterized by their frequency of oscillation, phase characteristics, dopamine dependency and topography. To this end we took recordings from macroelectrodes (MEs) inserted into the subthalamic nucleus (STN) in eight awake patients following functional neurosurgery for Parkinson's disease. An EEG was also recorded, as were the signals from MEs in the globus pallidus interna (GPi) in two of the cases. Coherence between EEG and ME potentials was apparent in three major frequency bands, 2-10 Hz, 10-30 Hz and 70-85 Hz. These rhythmic activities differed in their cortical topography, although coherence was always strongest over the midline. Coherence between EEG and ME potentials in the 70-85 Hz band was only recorded in patients treated with levodopa. Cortical activity phase led that in the basal ganglia in those oscillatory activities with frequencies <30 Hz. In contrast, STN and GPi phase led cortex in the 70-85 Hz band. The temporal differences in the way in which cortical activity led or lagged behind that in STN/GPi were similar, around 20 ms, regardless of the overall direction of information flow and frequency band. We conclude that the basal ganglia may receive multiple cortical inputs at frequencies <30 Hz and, in the presence of dopaminergic activity, produce a high frequency drive back to the cerebral cortex, in particular the supplementary motor area (SMA).

The minicolumn hypothesis in neuroscience

Abstract: The minicolumn is a continuing source of research and debate more than half a century after it was identified as a component of brain organization. The minicolumn is a sophisticated local network that contains within it the elements for redundancy and plasticity. Although it is sometimes compared to subcortical nuclei, the design of the minicolumn is a distinctive form of module that has evolved specifically in the neocortex. It unites the horizontal and vertical components of cortex within the same cortical space. Minicolumns are often considered highly repetitive, even clone-like, units. However, they display considerable heterogeneity between areas and species, perhaps even within a given macrocolumn. Despite a growing recognition of the anatomical basis of the cortical minicolumn, as well as its physiological properties, the potential of the minicolumn has not been exploited in fields such as comparative neuroanatomy, abnormalities of the brain and mind, and evolution.

Congenital amusia: a group study of adults afflicted with a music-specific disorder.

Abstract: The condition of congenital amusia, commonly known as tone-deafness, has been described for more than a century, but has received little empirical attention. In the present study, a research effort has been made to document in detail the behavioural manifestations of congenital amusia. A group of 11 adults, fitting stringent criteria of musical disabilities, were examined in a series of tests originally designed to assess the presence and specificity of musical disorders in brain-damaged patients. The results show that congenital amusia is related to severe deficiencies in processing pitch variations. The deficit extends to impairments in music memory and recognition as well as in singing and the ability to tap in time to music. Interestingly, the disorder appears specific to the musical domain. Congenital amusical individuals process and recognize speech, including speech prosody, common environmental sounds and human voices, as well as control subjects. Thus, the present study convincingly demonstrates the existence of congenital amusia as a new class of learning disabilities that affect musical abilities.

Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers.

Abstract: A neurological syndrome involving progressive action tremor with ataxia, cognitive decline and generalized brain atrophy has been described recently in some adult males with pre-mutation alleles of the fragile X syndrome (FXS) fragile X mental retardation gene (FMR1). Neurohistological studies have now been performed on the brains of four elderly premutation carriers, not reported previously, who displayed the neurological phenotype. Eosinophilic, intranuclear inclusions were present in both neuronal and astrocytic nuclei of the cortex in all four individuals. Systematic analysis of the brains of two of these carriers demonstrated the presence of the intranuclear inclusions throughout the cerebrum and brainstem, being most numerous in the hippocampal formation. The cerebellum displayed marked dropout of Purkinje cells, Purkinje axonal torpedoes and Bergmann gliosis. Intranuclear inclusions were absent from Purkinje cells, although they were present in a small number of neurones in the dentate nucleus and diffusely in cerebellar astrocytes. The presence of inclusions in the brains of all four FXS carriers with the neurological findings provides further support for a unique clinical entity associated with pre-mutation FMR1 alleles. The origin of the inclusions is unknown, although elevated FMR1 mRNA levels in these pre-mutation carriers may lead to the neuropathological changes.

An fMRI study of intentional and unintentional (embarrassing) violations of social norms

Abstract: The aim of this investigation was to identify neural systems supporting the processing of intentional and unintentional transgressions of social norms. Using event-related fMRI, we addressed this question by comparing neural responses to stories describing normal behaviour, embarrassing situations or violations of social norms. Processing transgressions of social norms involved systems previously reported to play a role in representing the mental states of others, namely medial prefrontal and temporal regions. In addition, the processing of transgressions of social norms involved systems previously found to respond to aversive emotional expressions (in particular angry expressions); namely lateral orbitofrontal cortex (Brodmann area 47) and medial prefrontal cortex. The observed responses were similar for both intentional and unintentional social norm violations, albeit more pronounced for the intentional norm violations. These data suggest that social behavioural problems in patients with frontal lobe lesions or fronto-temporal dementia may be a consequence of dysfunction within the systems identified in light of their possible role in processing whether particular social behaviours are, or are not, appropriate.

Brain anatomy and sensorimotor gating in Asperger’s syndrome

Abstract: Asperger's syndrome (an autistic disorder) is characterized by stereotyped and obsessional behaviours, and pervasive abnormalities in socio-emotional and communicative behaviour. These symptoms lead to social exclusion and a significant healthcare burden; however, their neurobiological basis is poorly understood. There are few studies on brain anatomy of Asperger's syndrome, and no focal anatomical abnormality has been reliably reported from brain imaging studies of autism, although there is increasing evidence for differences in limbic circuits. These brain regions are important in sensorimotor gating, and impaired 'gating' may partly explain the failure of people with autistic disorders to inhibit repetitive thoughts and actions. Thus, we compared brain anatomy and sensorimotor gating in healthy people with Asperger's syndrome and controls. We included 21 adults with Asperger's syndrome and 24 controls. All had normal IQ and were aged 18-49 years. We studied brain anatomy using quantitative MRI, and sensorimotor gating using prepulse inhibition of startle in a subset of 12 individuals with Asperger's syndrome and 14 controls. We found significant age-related differences in volume of cerebral hemispheres and caudate nuclei (controls, but not people with Asperger's syndrome, had age-related reductions in volume). Also, people with Asperger's syndrome had significantly less grey matter in fronto-striatal and cerebellar regions than controls, and widespread differences in white matter. Moreover, sensorimotor gating was significantly impaired in Asperger's syndrome. People with Asperger's syndrome most likely have generalized alterations in brain development, but this is associated with significant differences from controls in the anatomy and function of specific brain regions implicated in behaviours characterizing the disorder. We hypothesize that Asperger's syndrome is associated with abnormalities in fronto-striatal pathways resulting in defective sensorimotor gating, and consequently characteristic difficulties inhibiting repetitive thoughts, speech and actions.

Motor cortical disinhibition in the unaffected hemisphere after unilateral cortical stroke

Abstract: Following a hemispheric stroke, various degrees of neuronal reorganization around the lesion occur immediately after disease onset and thereafter up to several months. These include transcallosal excitability, changes of the intact motor cortex and ipsilateral motor responses after transcranial magnetic stimulation (TMS) on the intact hemisphere. To elucidate the relationship between lesion localization and motor cortex excitability (intracortical inhibition; ICI) in the intact hemisphere, we applied a paired conditioning-test TMS paradigm in 12 patients with unilateral cortical stroke (cortical group) and nine patients with subcortical stroke caudal to the corpus callosum (subcortical group), with interstimulus intervals varying from 1 to 10 ms. All patients exhibited unilateral complete hand palsy. ICI was significantly less in the cortical group than in age-matched healthy control subjects. It was especially more marked in the cortical group patients with a disease duration of less than 4 months after onset. Patients in the cortical group with a duration longer than 4 months showed a tendency for ICI to be normalized, and there was a significant correlation between ICI and disease duration. Patients in the subcortical group showed normal excitability curves. All patients in the cortical group showed no transcallosal inhibition (TCI) in the active unaffected hand muscle after TMS of the affected motor cortex, whereas all the subcortical patients showed some TCI. No ipsilateral motor responses were elicited in the paretic hand in any of the patients. The reduced ICI in the cortical group might have been a result of disruption of TCI. The normalization of ICI in the patients with longer disease duration and the normal ICI in the subcortical group patients do not support the functional significance of motor cortex hyperexcitability in the unaffected hemisphere, at least in a patient population with poor motor recovery.

Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy

Abstract: Epilepsy is resistant to drug treatment in about one-third of cases, but the mechanisms underlying this drug resistance are not understood. In cancer, drug resistance has been studied extensively. Amongst the various resistance mechanisms, overexpression of drug resistance proteins, such as multi-drug resistance gene-1 P-glycoprotein (MDR1) and multidrug resistance-associated protein 1 (MRP1), has been shown to correlate with cellular resistance to anticancer drugs. Previous studies in human epilepsy have shown that MDR1 and MRP1 may also be overexpressed in brain tissue from patients with refractory epilepsy; expression has been shown in glia and neurones, which do not normally express these proteins. We examined expression of MDR1 and MRP1 in refractory epilepsy from three common causes, dysembryoplastic neuroepithelial tumours (DNTs; eight cases), focal cortical dysplasia (FCD; 14 cases) and hippocampal sclerosis (HS; eight cases). Expression was studied immunohistochemically in lesional tissue from therapeutic resections and compared with expression in histologically normal adjacent tissue. With the most sensitive antibodies, in all eight DNT cases, reactive astrocytes within tumour nodules expressed MDR1 and MRP1. In five of eight HS cases, reactive astrocytes within the gliotic hippocampus expressed MDR1 and MRP1. Of 14 cases of FCD, MDR1 and MRP1 expression was noted in reactive astrocytes in all cases. In five FCD cases, MRP1 expression was also noted in dysplastic neurones. In FCD and DNTs, accentuation of reactivity was noted around lesional vessels. Immunoreactivity was always more frequent and intense in lesional reactive astrocytes than in glial fibrillary acidic protein-positive reactive astrocytes in adjacent histologically normal tissue. MDR1 is able to transport some antiepileptic drugs (AEDs), and MRP1 may also do so. The overexpression of these drug resistance proteins in tissue from patients with refractory epilepsy suggests one possible mechanism for drug resistance in patients with these pathologies. We propose that overexpressed resistance proteins lower the interstitial concentration of AEDs in the vicinity of the epileptogenic pathology and thereby render the epilepsy caused by these pathologies resistant to treatment with AEDs.