Showing papers in "Brain in 2003"

Theories of developmental dyslexia: insights from a multiple case study of dyslexic adults

Abstract: A multiple case study was conducted in order to assess three leading theories of developmental dyslexia: (i) the phonological theory, (ii) the magnocellular (auditory and visual) theory and (iii) the cerebellar theory. Sixteen dyslexic and 16 control university students were administered a full battery of psychometric, phonological, auditory, visual and cerebellar tests. Individual data reveal that all 16 dyslexics suffer from a phonological deficit, 10 from an auditory deficit, four from a motor deficit and two from a visual magnocellular deficit. Results suggest that a phonological deficit can appear in the absence of any other sensory or motor disorder, and is sufficient to cause a literacy impairment, as demonstrated by five of the dyslexics. Auditory disorders, when present, aggravate the phonological deficit, hence the literacy impairment. However, auditory deficits cannot be characterized simply as rapid auditory processing problems, as would be predicted by the magnocellular theory. Nor are they restricted to speech. Contrary to the cerebellar theory, we find little support for the notion that motor impairments, when found, have a cerebellar origin or reflect an automaticity deficit. Overall, the present data support the phonological theory of dyslexia, while acknowledging the presence of additional sensory and motor disorders in certain individuals.

Human cingulate cortex and autonomic control: converging neuroimaging and clinical evidence

Abstract: Human anterior cingulate function has been explained primarily within a cognitive framework. We used functional MRI experiments with simultaneous electrocardiography to examine regional brain activity associated with autonomic cardiovascular control during performance of cognitive and motor tasks. Using indices of heart rate variability, and high- and low-frequency power in the cardiac rhythm, we observed activity in the dorsal anterior cingulate cortex (ACC) related to sympathetic modulation of heart rate that was dissociable from cognitive and motor-related activity. The findings predict that during effortful cognitive and motor behaviour the dorsal ACC supports the generation of associated autonomic states of cardiovascular arousal. We subsequently tested this prediction by studying three patients with focal damage involving the ACC while they performed effortful cognitive and motor tests. Each showed abnormalities in autonomic cardiovascular responses with blunted autonomic arousal to mental stress when compared with 147 normal subjects tested in identical fashion. Thus, converging neuroimaging and clinical findings suggest that ACC function mediates context-driven modulation of bodily arousal states.

Lead neurotoxicity in children: basic mechanisms and clinical correlates.

Abstract: Lead has been recognized as a poison for millennia and has been the focus of public health regulation in much of the developed world for the better part of the past century. The nature of regulation has evolved in response to increasing information provided by vigorous scientific investigation of lead's effects. In recognition of the particular sensitivity of the developing brain to lead's pernicious effects, much of this legislation has been addressed to the prevention of childhood lead poisoning. The present review discusses the current state of knowledge concerning the effects of lead on the cognitive development of children. Addressed are the reasons for the child's exquisite sensitivity, the behavioural effects of lead, how these effects are best measured, and the long-term outlook for the poisoned child. Of particular importance are the accumulating data suggesting that there are toxicological effects with behavioural concomitants at exceedingly low levels of exposure. In addition, there is also evidence that certain genetic and environmental factors can increase the detrimental effects of lead on neural development, thereby rendering certain children more vulnerable to lead neurotoxicity. The public health implications of these findings are discussed.

Early Clinical Predictors and Progression of Irreversible Disability in Multiple Sclerosis: an Amnesic Process

Abstract: Prognosis of multiple sclerosis is highly variable. Clinical variables have been identified that are assessable early in the disease and are predictors of the time from the disease onset to the onset of irreversible disability. Our objective was to determine if these clinical variables still have an effect after the first stages of disability have been reached. We determined the dates of disease onset and assignment of scores of irreversible disability in 1844 patients with multiple sclerosis. We used three scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: 4 (limited walking but without aid); 6 (walking with unilateral aid); and 7 (wheelchair bound). We used Kaplan-Meier analyses and Cox regression models to determine the influence of the clinical variables on the time to disability onset. Median times from onset of multiple sclerosis to assignment of a score of 4, 6 and 7 were significantly influenced by gender, age, symptoms and course (relapsing-remitting or progressive) at onset of the disease, degree of recovery from the first relapse, time to a second neurological episode, and the number of relapses in the first 5 years of the disease. Similarly, times from onset of multiple sclerosis to a score of 6 and 7 were influenced by time to a score of 4. In contrast, none of the variables substantially affected the time from a score of 4 to a score of 6 or 7, or from a score of 6 to a score of 7. Early assessable clinical variables significantly influence the time from the onset of multiple sclerosis to the assignment of a disability score of 4, but not the subsequent progression of irreversible disability.

Neural correlates of motor recovery after stroke: a longitudinal fMRI study.

Abstract: Recovery of motor function after stroke may occur over weeks or months and is often attributed to cerebral reorganization. We have investigated the longitudinal relationship between recovery after stroke and task-related brain activation during a motor task as measured using functional MRI (fMRI). Eight first-ever stroke patients presenting with hemiparesis resulting from cerebral infarction sparing the primary motor cortex, and four control subjects were recruited. Subjects were scanned on a number of occasions whilst performing an isometric dynamic visually paced hand grip task. Recovery in the patient group was assessed using a battery of outcome measures at each time point. Task-related brain activations decreased over sessions as a function of recovery in a number of primary and non-primary motor regions in all patients, but no session effects were seen in the controls. Furthermore, consistent decreases across sessions correlating with recovery were seen across the whole patient group independent of rate of recovery or initial severity, in primary motor cortex, premotor and prefrontal cortex, supplementary motor areas, cingulate sulcus, temporal lobe, striate cortex, cerebellum, thalamus and basal ganglia. Although recovery-related increases were seen in different brain regions in four patients, there were no consistent effects across the group. These results further our understanding of the recovery process by demonstrating for the first time a clear temporal relationship between recovery and task-related activation of the motor system after stroke.

Occipito-temporal connections in the human brain

Abstract: Diffusion tensor MRI (DT‐MRI) provides information about the structural organization and orientation of white matter fibres and, through the technique of ‘tractography’, reveals the trajectories of cerebral white matter tracts. We used tractography in the living human brain to address the disputed issue of the nature of occipital and temporal connections. Classical anatomical studies described direct fibre connections between occipital and anterior temporal cortex in a bundle labelled the inferior longitudinal fasciculus (ILF). However, their presence has been challenged by more recent evidence suggesting that connections between the two regions are entirely indirect, conveyed by the occipito‐temporal projection system—a chain of U‐shaped association fibres. DT‐MRI data were collected from 11 right‐handed healthy subjects (mean age 33.3 ± 4.7 years). Each data set was co‐registered with a standard MRI brain template, and a group‐averaged DT‐MRI data set was created. ‘Virtual’ in vivo dissection of occipito‐temporal connections was performed in the group‐averaged data. Further detailed virtual dissection was performed on the single brain data sets. Our results suggest that in addition to the indirect connections of the occipito‐temporal projection system: (i) a major associative connection between the occipital and anterior temporal lobe is provided by a fibre bundle whose origin, course and termination are consistent with classical descriptions of the ILF in man and with monkey visual anatomy; (ii) the tractography‐defined ILF is structurally distinct from fibres of the optic radiation and from U‐shaped fibres connecting adjacent gyri; (iii) it arises in extrastriate visual ‘association’ areas; and (iv) it projects to lateral and medial anterior temporal regions. While the function of the direct ILF pathway is unclear, it appears to mediate the fast transfer of visual signals to anterior temporal regions and neuromodulatory back‐projections from the amygdala to early visual areas. Future tractography studies of patients with occipito‐temporal disconnection syndromes may help define the functional roles of the direct and indirect occipito‐temporal pathways.

Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation.

Abstract: Frontal lobe activity during pain is generally linked to attentional processing. We addressed the question of whether 'bottom-up' processing and 'top-down' modulation of nociceptive information dissociate anatomically within the frontal lobe by using PET scanning during painful thermal stimulation of normal and capsaicin-treated skin. We showed recently that pain following normally non-painful heat stimuli on chemically irritated skin (heat allodynia) uniquely engages extensive areas of the bilateral dorsolateral prefrontal (DLPFC), ventral/orbitofrontal (VOFC) and perigenual anterior cingulate (ACC) cortices. Here, we applied principal component analysis (PCA) and multiple regression analysis to study the covariance structure of the volumes of interest (VOI) activated specifically during heat allodynia in 14 male healthy subjects and evaluated the relationship of these VOI to ratings of pain intensity and affect. Results yielded a primary principal component (PC) that correlated positively with intensity and unpleasantness and accounted for activity in the medial thalamus, bilateral anterior insula, ventral striatum, perigenual ACC and bilateral VOFC. Activities in the right and left DLPFC loaded on separate PC and correlated negatively with perceived intensity and unpleasantness. The inter-regional correlation of midbrain and medial thalamic activity was significantly reduced during high left DLPFC activity, suggesting that its negative correlation with pain affect may result from dampening of the effective connectivity of the midbrain-medial thalamic pathway. In contrast, right DLPFC activity was associated with a weakened relationship of the anterior insula with both pain intensity and affect. We propose that the DLPFC exerts active control on pain perception by modulating corticosubcortical and corticocortical pathways.

The anatomy of visual neglect

Abstract: The brain regions that are critically associated with visual neglect have become intensely disputed. In particular, one study of middle cerebral artery (MCA) stroke patients has claimed that the key brain region associated with neglect is the mid portion of the superior temporal gyrus (STG), on the lateral surface of the right hemisphere, rather than the posterior parietal lobe. Such a result has wide-ranging implications for both our understanding of the normal function these cortical areas and the potential mechanisms underlying neglect. Here, we use novel high resolution MRI protocols to map the lesions of 35 right-hemisphere patients who had suffered either MCA or posterior cerebral artery (PCA) territory stroke. For patients with MCA territory strokes, the critical area involved in all neglect patients was the angular gyrus of the inferior parietal lobe (IPL). Although the STG was damaged in half of our MCA neglect patients, it was spared in the rest. For PCA territory strokes, all patients with neglect had lesions involving the parahippocampal region, on the medial surface of the temporal lobe. PCA patients without neglect did not have damage to this area. We conclude that damage to two posterior regions, one in the IPL and the other in the medial temporal lobe, is associated with neglect. Although some neglect patients do have damage to the STG, our findings challenge the recent influential proposal that lesions of this area are critically associated with neglect. Instead, our results implicate the angular gyrus and parahippocampal region in this role.

Cannabis and the brain

Abstract: Summary The active compound in herbal cannabis, D 9 -tetrahydrocannabinol, exerts all of its known central effects through the CB1 cannabinoid receptor. Research on cannabinoid mechanisms has been facilitated by the availability of selective antagonists acting at CB1 receptors and the generation of CB1 receptor knockout mice. Particularly important classes of neurons that express high levels of CB1 receptors are GABAergic interneurons in hippocampus, amygdala and cerebral cortex, which also contain the neuropeptides cholecystokinin. Activation of CB1 receptors leads to inhibition of the release of amino acid and monoamine neurotransmitters. The lipid derivatives anandamide and 2-arachidonylglycerol act as endogenous ligands for CB1 receptors (endocannabinoids). They may act as retrograde synaptic mediators of the phenomena of depolarizationinduced suppression of inhibition or excitation in hippocampus and cerebellum. Central effects of cannabinoids include disruption of psychomotor behaviour, shortterm memory impairment, intoxication, stimulation of appetite, antinociceptive actions (particularly against pain of neuropathic origin) and anti-emetic effects. Although there are signs of mild cognitive impairment in chronic cannabis users there is little evidence that such impairments are irreversible, or that they are accompanied by drug-induced neuropathology. A proportion of regular users of cannabis develop tolerance and dependence on the drug. Some studies have linked chronic use of cannabis with an increased risk of psychiatric illness, but there is little evidence for any causal link. The potential medical applications of cannabis in the treatment of painful muscle spasms and other symptoms of multiple sclerosis are currently being tested in clinical trials. Medicines based on drugs that enhance the function of endocannabinoids may offer novel therapeutic approaches in the future.

Changes in emotion after circumscribed surgical lesions of the orbitofrontal and cingulate cortices

Abstract: Summary To analyse the functions of different parts of the prefrontal cortex in emotion, patients with different prefrontal surgical excisions were compared on four measures of emotion: voice and face emotional expression identification, social behaviour, and the subjective experience of emotion. Some patients with bilateral lesions of the orbitofrontal cortex (OFC) had deficits in voice and face expression identification, and the group had impairments in social behaviour and significant changes in their subjective emotional state. Some patients with unilateral damage restricted to the OFC also had deficits in voice expression identification, and the group did not have significant changes in social behaviour or in their subjective emotional state. Patients with unilateral lesions of the antero-ventral part of the anterior cingulate cortex (ACC) and/or medial Brodmann area (BA) 9 were, in some cases, impaired on voice and face expression identification, had some change in social behaviour, and had significant changes in their subjective emotional state. Patients with unilateral lesions of the OFC and of the ACC and/or medial BA 9 were, in some cases, impaired on voice and face expression identification, had some changes in social behaviour, and had significant changes in their subjective emotional state. Patients with dorsolateral prefrontal cortex lesions or with medial lesions outside ACC and medial BA 9 areas (dorsolateral/other medial group) were unimpaired on any of these measures of emotion. In all cases in which voice expression identification was impaired, there were no deficits in control tests of the discrimination of unfamiliar voices and the recognition of environmental sounds. Thus bilateral or unilateral lesions circumscribed surgically within the OFC can impair emotional voice and/or face expression identification, but significant changes in social behaviour and in subjective emotional state are related to bilateral lesions. Importantly, unilateral lesions of the ACC (including some of medial BA 9) can produce voice and/or face expression identification deficits, and marked changes in subjective emotional state. These findings with surgically circumscribed lesions show that within the prefrontal cortex, both the OFC and the ACC/medial BA 9 region are involved in a number of aspects of emotion in humans including emotion identification, social behaviour and subjective emotional state, and that the dorsolateral prefrontal areas are not involved in emotion in these ways.

A network of occipito-temporal face-sensitive areas besides the right middle fusiform gyrus is necessary for normal face processing.

Abstract: Neuroimaging studies have identified at least two bilateral areas of the visual extrastriate cortex that respond more to pictures of faces than objects in normal human subjects in the middle fusiform gyrus [the 'fusiform face area' (FFA)] and, more posteriorly, in the inferior occipital cortex ['occipital face area' (OFA)], with a right hemisphere dominance. However, it is not yet clear how these regions interact which each other and whether they are all necessary for normal face perception. It has been proposed that the right hemisphere FFA acts as an isolated ('modular') processing system for faces or that this region receives its face-sensitive inputs from the OFA in a feedforward hierarchical model of face processing. To test these proposals, we report a detailed neuropsychological investigation combined with a neuroimaging study of a patient presenting a deficit restricted to face perception, consecutive to bilateral occipito-temporal lesions. Due to the asymmetry of the lesions, the left middle fusiform gyrus and the right inferior occipital cortex were damaged but the right middle fusiform gyrus was structurally intact. Using functional MRI, we disclosed a normal activation of the right FFA in response to faces in the patient despite the absence of any feedforward inputs from the right OFA, located in a damaged area of cortex. Together, these findings show that the integrity of the right OFA is necessary for normal face perception and suggest that the face-sensitive responses observed at this level in normal subjects may arise from feedback connections from the right FFA. In agreement with the current literature on the anatomical basis of prosopagnosia, it is suggested that the FFA and OFA in the right hemisphere and their re-entrant integration are necessary for normal face processing.

Motor learning elicited by voluntary drive

Abstract: Summary Motor training consisting of voluntary movements leads to performance improvements and results in characteristic reorganizational changes in the motor cortex. It has been proposed that repetition of passively elicited movements could also lead to improvements in motor performance. In this study, we compared behavioural gains, changes in functional MRI (fMRI) activation in the contralateral primary motor cortex (cM1) and in motor cortex excitability measured with transcranial magnetic stimulation (TMS) after a 30 min training period of either voluntarily (active) or passively (passive) induced wrist movements, when alertness and kinematic aspects of training were controlled. During active training, subjects were instructed to perform voluntary wrist flexion‐extension movements of a specified duration (target window 174‐186 ms) in an articulated splint. Passive training consisted of wrist flexion‐ extension movements elicited by a torque motor, of the same amplitude and duration range as in the active task. fMRI activation and TMS parameters of motor cortex excitability were measured before and after each training type. Motor performance, measured as the number of movements that hit the target window duration, was significantly better after active than after passive training. Both active and passive movements performed during fMRI measurements activated cM1. Active training led to more prominent increases in (i) fMRI activation of cM1; (ii) recruitment curves (TMS); and (iii) intracortical facilitation (TMS) than passive training. Therefore, a short period of active motor training is more effective than passive motor training in eliciting performance improvements and cortical reorganization. This result is consistent with the concept of a pivotal role for voluntary drive in motor learning and neurorehabilitation.

Ventromedial frontal cortex mediates affective shifting in humans: evidence from a reversal learning paradigm

Abstract: Summary How do the frontal lobes support behavioural flexibility? One key element is the ability to adjust responses when the reinforcement value of stimuli change. In monkeys, this ability—a form of affective shifting known as reversal learning—depends on orbitofrontal cortex. The present study examines the anatomical bases of reversal learning in humans. Subjects with lesions of the ventromedial prefrontal cortex were compared with a group with dorsolateral frontal lobe damage, as well as with normal controls on a simple reversal learning task. Neither form of frontal damage affected initial stimulus‐reinforcement learning; ventromedial frontal damage selectively impaired reversal learning.

Neural correlates of outcome after stroke: a cross-sectional fMRI study

Abstract: Recovery of motor function after stroke may occur over weeks or months and is often attributed to neuronal reorganization. Functional imaging studies investigating patients who have made a good recovery after stroke have suggested that recruitment of other motor-related networks underlies this recovery. However, patients with less complete recovery have rarely been studied, or else the degree of recovery has not been taken into account. We set out to investigate the relationship between the degree of recovery after stroke and the pattern of recruitment of brain regions during a motor task as measured using functional MRI. We recruited 20 patients who were at least 3 months after their first ever stroke, and 26 right-handed age-matched control subjects. None of our patients had infarcts involving the hand region of the primary motor cortex. All subjects were scanned whilst performing an isometric, dynamic visually paced handgrip task. The degree of functional recovery of each patient was assessed using a battery of outcome measures. Single-patient versus control group analysis revealed that patients with poor recovery were more likely to recruit a number of motor-related brain regions over and above those seen in the control group during the motor task, whereas patients with more complete recovery were more likely to have 'normal' task-related brain activation. Across the whole patient group and across stroke subtypes, we were able to demonstrate a negative correlation between outcome and the degree of task-related activation in regions such as the supplementary motor area, cingulate motor areas, premotor cortex, posterior parietal cortex, and cerebellum. This negative correlation was also seen in parts of both contralateral and ipsilateral primary motor cortex. These results further our understanding of the recovery process by demonstrating for the first time a clear relationship between task-related activation of the motor system and outcome after stroke.

Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis.

Abstract: The term seronegative myasthenia gravis (SNMG) refers to the generalized disease without detectable anti-acetylcholine receptor (anti-AChR) antibodies. In these patients, IgG antibodies against the muscle-specific kinase (MuSK) have been described, which reduced agrin-induced AChR clustering in vitro. We have assayed anti-MuSK antibodies in 78 patients with SNMG, who have been followed for many years in our Institution. Here we describe the clinical phenotype of the 37 patients whose results were positive on this assay. MG with anti-MuSK antibodies was characterized by a striking prevalence of female patients (eight men and 29 women). Age of onset ranged from 6 to 68 years, with 56.8% of patients presenting under 40 years of age. All these patients shared a similar pattern of muscle weakness, with prevalent involvement of cranial and bulbar muscles and a high frequency of respiratory crises; the involvement of limb muscles was comparatively less severe and inconsistent. Single-fibre-EMG confirmed the most sensitive examination in the EMG diagnosis of MuSK-positive disease, while, owing to weakness topography, repetitive nerve stimulation in limb muscles was diagnostic in 56.8% of cases. The effect of edrophonium (or neostigmine) injection was equivocal or negative in 11 of 37 patients (29.7%), and the response to oral pyridostigmine was even more unsatisfactory, ranging from mild benefit to overt intolerance. In thymectomized patients, thymus was normal for age or atrophied, and no benefit from surgery was noticed. Thirty-five of 37 patients were given immunosuppressive therapy and 22 received plasma-exchange. The course of the disease was often characterized by periodic exacerbation phases requiring hospitalization and even assisted ventilation; plasma-exchange produced marked improvement in these cases. At the end of the observation period, most patients, although improved, were still symptomatic, having developed permanent facial and pharyngeal weakness together with some atrophy of facial muscles. MuSK-negative disease was comparatively more heterogeneous. Most patients were affected with mild to moderate symptoms and responded well to pharmacological treatment; however, a few subjects in this group had severe refractory disease, poorly responsive to both acetylcholinesterase inhibitors and immunosuppressants.

Striatal dopamine release induced by repetitive transcranial magnetic stimulation of the human motor cortex.

Abstract: Summary Brain dopamine is implicated in the regulation of movement, attention, reward and learning. Dysfunction of dopamine plays a role in Parkinson’s disease, schizophrenia and drug addiction. It is released in the striatum when dopamine neurons in the midbrain undergo burst firing. Several animal studies have shown that dopamine can also be released under direct control of glutamatergic corticostriatal efferents. However, the existence and physiological significance of this mode of action remain controversial. We have shown previously that repetitive transcranial magnetic stimulation (rTMS) of the human prefrontal cortex led to focal dopamine release in the ipsilateral caudate nucleus, supporting the corticostriatal mode of dopamine release. Using the same experimental approach, we sought to confirm this hypothesis. We used [ 11 C]raclopride and PET to measure changes in extracellular dopamine concentration following rTMS of the motor cortex in six healthy human subjects. rTMS of the left primary motor cortex caused a reduction in [ 11 C]raclopride binding in the left putamen compared with rTMS of the left occipital cortex. There were no changes in binding in the right putamen, caudate nucleus or nucleus accumbens. The area of statistically significant change in binding corresponded closely to the known projection zone of corticostriatal efferents originating in monkey motor cortex. This finding has implications for the functional role of subcortical dopamine.

Exploring the neurological substrate of emotional and social intelligence.

Abstract: The somatic marker hypothesis posits that deficits in emotional signalling (somatic states) lead to poor judgment in decision-making, especially in the personal and social realms. Similar to this hypothesis is the concept of emotional intelligence, which has been defined as an array of emotional and social abilities, competencies and skills that enable individuals to cope with daily demands and be more effective in their personal and social life. Patients with lesions to the ventromedial (VM) prefrontal cortex have defective somatic markers and tend to exercise poor judgment in decision-making, which is especially manifested in the disadvantageous choices they typically make in their personal lives and in the ways in which they relate with others. Furthermore, lesions to the amygdala or insular cortices, especially on the right side, also compromise somatic state activation and decision-making. This suggests that the VM, amygdala and insular regions are part of a neural system involved in somatic state activation and decision-making. We hypothesized that the severe impairment of these patients in real-life decision-making and an inability to cope effectively with environmental and social demands would be reflected in an abnormal level of emotional and social intelligence. Twelve patients with focal, stable bilateral lesions of the VM cortex or with right unilateral lesions of the amygdala or the right insular cortices, were tested on the Emotional Quotient Inventory (EQ-i), a standardized psychometric measure of various aspects of emotional and social intelligence. We also examined these patients with various other procedures designed to measure decision-making (the Gambling Task), social functioning, as well as personality changes and psychopathology; standardized neuropsychological tests were applied to assess their cognitive intelligence, executive functioning, perception and memory as well. Their results were compared with those of 11 patients with focal, stable lesions in structures outside the neural circuitry thought to mediate somatic state activation and decision-making. Only patients with lesions in the somatic marker circuitry revealed significantly low emotional intelligence and poor judgment in decision-making as well as disturbances in social functioning, in spite of normal levels of cognitive intelligence (IQ) and the absence of psychopathology based on DSM-IV criteria. The findings provide preliminary evidence suggesting that emotional and social intelligence is different from cognitive intelligence. We suggest, moreover, that the neural systems supporting somatic state activation and personal judgment in decision-making may overlap with critical components of a neural circuitry subserving emotional and social intelligence, independent of the neural system supporting cognitive intelligence.

The cerebral oscillatory network of parkinsonian resting tremor

Abstract: Data from experiments in MPTP monkeys as well as from invasive and non-invasive recordings in patients with Parkinson's disease suggest an abnormal synchronization of neuronal activity in the generation of resting tremor in Parkinson's disease. In six patients with tremor-dominant idiopathic Parkinson's disease, we recorded simultaneously surface electromyograms (EMGs) of hand muscles, and brain activity with a whole-head magnetoencephalography (MEG) system. Using a recently developed analysis tool (Dynamic Imaging of Coherent Sources; DICS), we determined cerebro-muscular and cerebro-cerebral coherence as well as the partial coherence between cerebral areas and muscle, and localized coherent sources within the individual MRI scans. The phase lag between the EMG and cerebral activity was determined by means of a Hilbert transform of both signals. After overnight withdrawal from medication, patients showed typical Parkinson's disease resting tremor (4-6 Hz). This tremor was associated with strong coherence between the EMG of forearm muscles and activity in the contralateral primary motor cortex (M1) at tremor frequency but also at double tremor frequency. Phase lags between M1 activity and EMG were between 15 and 25 ms (M1 activity leading) at single, but also at double tremor frequency, corresponding well to the corticomuscular conduction time. Furthermore, significant coherence was observed between M1 and medial wall areas (cingulate/supplementary motor area; CMA/SMA), lateral premotor cortex (PM), diencephalon, secondary somatosensory cortex (SII), posterior parietal cortex (PPC) and the contralateral cerebellum at single tremor and, even stronger at double tremor frequency. Spectra of coherence between thalamic activity and cerebellum as well as several brain areas revealed additional broad peaks around 20 Hz. Power spectral analysis of activity in all central areas indicated the strongest frequency components at double tremor frequency. Partial coherence analysis and the calculation of phase shifts revealed a strong bidirectional coupling between the EMG and diencephalic activity and a direct afferent coupling between the EMG and SII and the PPC. In contrast, the cerebellum, SMA/CMA and PM show little evidence for direct coupling with the peripheral EMG but seem to be connected with the periphery via other cerebral areas (e.g. M1). In summary, our results demonstrate tremor-related oscillatory activity within a cerebral network, with abnormal coupling in a cerebello-diencephalic-cortical loop and cortical motor (M1, SMA/CMA, PM) and sensory (SII, PPC) areas contralateral to the tremor hand. The main frequency of cerebro-cerebral coupling corresponds to double the tremor frequency.

Staying on the job: the frontal lobes control individual performance variability.

Abstract: The causes of variability of performance by individual subjects have rarely been investigated, although excessive variability or inconsistency may be a functionally significant factor for many real-life activities. Our objective was to determine whether patients with focal frontal brain lesions have excessive individual performance variability. Thirty-six patients with focal frontal (n=25) or non-frontal (n=11) lesions were compared with 12 control subjects on different measures of intra-individual variability: dispersion within a testing session; and consistency across testing sessions. Four reaction time tasks, varying in levels of complexity and based on a model of detection using feature integration, were administered. Following the first test session, 22 patients and 10 controls returned for two subsequent test sessions, which permitted the assessment of consistency of performance. Measures of abnormal dispersion of performance on these tests were observed in frontal patients only (except those with exclusively inferior medial damage). Disturbances in consistency of performance were observed primarily in patients with frontal lesions. Damage to the frontal lobes impairs the stability of cognitive performance. Damage to different frontal regions causes different profiles of abnormal variability. Fluctuations in performance of a task may underlie some of the reported difficulties in daily tasks reported by patients with frontal injuries.

Ventral occipital lesions impair object recognition but not object-directed grasping: an fMRI study.

Abstract: Summary D.F., a patient with severe visual form agnosia, has been the subject of extensive research during the past decade. The fact that she could process visual input accurately for the purposes of guiding action despite being unable to perform visual discriminations on the same visual input inspired a novel interpretation of the functions of the two main cortical visual pathways or ‘streams’. Within this theoretical context, the authors proposed that D.F. had suffered severe bilateral damage to her occipitotemporal visual system (the ‘ventral stream’), while retaining the use of her occipitoparietal visual system (the ‘dorsal stream’). The present paper reports a direct test of this idea, which was initially derived from purely behavioural data, before the advent of modern functional neuroimaging. We used functional MRI to examine activation in her ventral and dorsal streams during object recognition and object-directed grasping tasks. We found that D.F. showed no difference in activation when presented with line drawings of common objects compared with scrambled line drawings in the lateral occipital cortex (LO) of the ventral stream, an area that responded differentially to these stimuli in healthy individuals. Moreover, highresolution anatomical MRI showed that her lesion corresponded bilaterally with the location of LO in healthy participants. The lack of activation with line drawings in D.F. mirrors her poor performance in identifying the objects depicted in the drawings. With coloured and greyscale pictures, stimuli that she can identify more often, D.F. did show some ventral-stream activation. These activations were, however, more widely distributed than those seen in control participants and did not include LO. In contrast to the absent or abnormal activation observed during these perceptual tasks, D.F. showed robust activation in the expected dorsal stream regions during object grasping, despite considerable atrophy in some regions of the parietal lobes. In particular, an area in the anterior intraparietal sulcus was activated more for grasping an object than for just reaching to that object, for both D.F. and controls. In conclusion, we have been able to confirm directly that D.F.’s visual form agnosia is associated with extensive damage to the ventral stream, and that her spared visuomotor skills are associated with visual processing in the dorsal stream.

Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients

Abstract: Paraneoplastic cerebellar degeneration (PCD) is a heterogeneous group of disorders characterized by subacute cerebellar ataxia, specific tumour types and (often) associated antineuronal antibodies. Nine specific antineuronal antibodies are associated with PCD. We examined the relative frequency of the antineuronal antibodies associated with PCD and compared the neurological symptoms and signs, associated tumours, disability and survival between groups of PCD with different antibodies. Also, we attempted to identify patient-, tumour- and treatment-related characteristics associated with functional outcome and survival. In a 12-year period, we examined >5000 samples for the presence of antineuronal antibodies. A total of 137 patients were identified with a paraneoplastic neurological syndrome and high titre (> or =400) antineuronal antibodies. Fifty (36%) of these patients had antibody-associated PCD, including 19 anti-Yo, 16 anti-Hu, seven anti-Tr, six anti-Ri and two anti-mGluR1. Because of the low number, the anti-mGluR1 patients were excluded from the statistical analysis. While 100% of patients with anti-Yo, anti-Tr and anti-mGluR1 antibodies suffered PCD, 86% of anti-Ri and only 18% of anti-Hu patients had PCD. All patients presented with subacute cerebellar ataxia progressive over weeks to months and stabilized within 6 months. The majority of patients in all antibody groups had both truncal and appendicular ataxia. The frequency of nystagmus and dysarthria was lower in anti-Ri patients (33 and 0%). Later in the course of the disease, involvement of non-cerebellar structures occurred most frequently in anti-Hu patients (94%). In 42 patients (84%), a tumour was detected. The most commonly associated tumours were gynaecological and breast cancer (anti-Yo and anti-Ri), lung cancer (anti-Hu) and Hodgkin's lymphoma (anti-Tr and anti-mGluR1). In one anti-Hu patient, a suspect lung lesion on CT scan disappeared while the PCD evolved. Seven patients improved by at least 1 point on the Rankin scale, while 16 remained stable and 27 deteriorated. All seven patients that improved received antitumour treatment for their underlying cancer, resulting in complete remission. The functional outcome was best in the anti-Ri patients, with three out of six improving neurologically and five were able to walk at the time of last follow-up or death. Only four out of 19 anti-Yo and four out of 16 anti-Hu patients remained ambulatory. Also, survival from time of diagnosis was significantly worse in the anti-Yo (median 13 months) and anti-Hu (median 7 months) patients compared with anti-Tr (median >113 months) and anti-Ri (median >69 months). Patients receiving antitumour treatment (with or without immunosuppressive therapy) lived significantly longer [hazard ratio (HR) 0.3; 95% confidence interval (CI) 0.1-0.6; P = 0.004]. Patients > or =60 years old lived somewhat shorter from time of diagnosis, although statistically not significant (HR 2.9; CI 1.0-8.5; P = 0.06).

Age‐related changes in the neural correlates of motor performance

Abstract: Age-related neurodegenerative and neurochemical changes are thought to underlie decline in motor and cognitive functions, but compensatory processes in cortical and subcortical function may allow maintenance of performance level in some people. Our objective was to investigate age-related changes in the motor system of the human brain using functional MRI. Twenty six right handed volunteers were scanned whilst performing an isometric, dynamic, visually paced hand grip task, using dominant (right) and non-dominant (left) hands in separate sessions. Hand grip with visual feedback activated a network of cortical and subcortical regions known to be involved in the generation of simple motor acts. In addition, activation was seen in a putative human 'grasping circuit', involving rostral ventral premotor cortex (Brodmann area 44) and intraparietal sulcus. Within this network, a number of regions were more likely to be activated the older the subject. In particular, age-related changes in task- specific activations were demonstrated in left deep anterior central sulcus when using the dominant or non-dominant hand. Additional age-related increases were seen in caudal dorsal premotor cortex, caudal cingulate sulcus, intraparietal sulcus, insula, frontal operculum and cerebellar vermis. We have demonstrated a clear age-related effect in the neural correlates of motor performance, and furthermore suggest that these changes are non-linear. These results support the notion that an adaptable and plastic motor network is able to respond to age-related degenerative changes in order to maintain performance levels.

Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study.

Abstract: Since 1994, a population-based study of frontotemporal dementia (FTD) in The Netherlands has aimed to ascertain all patients with FTD, and first prevalence estimates based on 74 patients were reported in 1998. Here, we present new prevalence estimates after expansion of our FTD population to 245 patients, with emphasis on the prevalence in the province Zuid-Holland where the main study centre is located. All neurologists and physicians in nursing homes received a yearly postal enquiry about suspected FTD cases. FTD was diagnosed in 245 patients according to the Lund-Manchester criteria, supported by neuroimaging and neuropsychology. tau mutation analysis was performed in a subgroup of 154 patients (63%), and 40 out of 98 patients (41%) who died during follow-up were autopsied during the course of the study. The prevalence of FTD in the province Zuid-Holland was 3.6 per 100,000 at age 50-59 years, 9.4 per 100,000 at age 60-69 years and 3.8 per 100,000 at age 70-79 years. The median age at onset of the 245 patients (51% female) was 58.0 years (range 33-80 years). Dementia in one or more first-degree family members was found in 43% of patients and mutation analysis of the tau gene showed mutations in 34 patients (19 P301L, five L315R, four G272V, four R406W, one Delta K280 and one S320F), all with a positive family history for dementia (14% of the total population, 32% of patients with a positive family history). Pathological findings in the 40 autopsied patients consisted of dementia lacking distinctive histology in 22%, FTD with ubiquitin-positive inclusions in 33%, Pick's disease in 15% and tauopathy in the remaining 30% of patients, with tau mutations identified in more than half of the latter patients. We conclude that the prevalence of FTD in The Netherlands is higher than previously reported, confirming that FTD is more common than was previously thought. The finding of tau mutations in 32% of patients with a positive family history for dementia justifies mutation screening in FTD patients with a positive family history, while tau mutations in non-familiar cases are rare.

Mesial temporal damage in temporal lobe epilepsy: a volumetric MRI study of the hippocampus, amygdala and parahippocampal region.

Abstract: Despite neuropathological and electrophysiological evidence for the involvement of parahippocampal structures in temporal lobe epilepsy (TLE), little attention has been paid to morphometric measurements of these structures in patients with TLE. Using high resolution MRI, we previously showed that the volume of the entorhinal cortex was decreased in patients with TLE. The purpose of this study was: (i) to determine whether changes in the volume of the perirhinal cortex and posterior parahippocampal cortex were detectable by MRI; and (ii) to study the distribution and degree of atrophy in mesial temporal structures including the hippocampal head, body and tail, amygdala, entorhinal cortex, perirhinal cortex and posterior parahippocampal cortex. MRI volumetric analysis was performed using a T(1)-weighted three-dimensional gradient echo sequence in 20 healthy subjects and 25 TLE patients with intractable TLE. In patients with either left or right TLE, the hippocampal head, body and tail and the entorhinal and perirhinal cortices ipsilateral to the seizure focus were significantly smaller than in normal controls. The mean volume of the posterior parahippocampal cortex was not different from that of normal controls. Within the hippocampus, the hippocampal head was more atrophic than the hippocampal body and hippocampal tail. Within the parahippocampal region, the entorhinal cortex was more severely affected than the perirhinal cortex. Our MRI results confirm pathological findings of damage in the mesial temporal lobe, involving not only the hippocampus and the amygdala, but also the entorhinal and perirhinal cortices. The pattern of atrophy may be explained by cell loss secondary to a disruption of entorhinal-hippocampal connections as a result of privileged electrical dialogue between these two structures.

Minimum birth prevalence of mitochondrial respiratory chain disorders in children

Abstract: Mitochondrial respiratory chain disorders comprise a group of perhaps several hundred different genetic diseases. Each individual disorder is rare, but collectively they account for substantial use of health care resources. However, few accurate data on prevalence are available due to problems such as variation in clinical presentation, age of onset, referral practices and limitations of diagnostic methodologies. With this retrospective study, we aimed to determine the minimum birth prevalence of respiratory chain disorders that have onset in childhood, that is the proportion of births that will have onset of symptoms caused by a respiratory chain defect by 16 years of age. Of the 1 706 694 children born in the three south-eastern states of Australia (New South Wales, Victoria and South Australia) between January 1st 1987 and December 31st 1996, samples from 430 were referred for investigation of a respiratory chain disorder. Definite diagnosis of a respiratory chain disorder was made in 86 cases based on defined clinical, pathological, enzyme and molecular criteria. Age at presentation ranged from 0 to 129 months (median 4 months). The total data set predicts a minimum birth prevalence for respiratory chain disorders in children of 5.0/100 000 [95% confidence interval (CI) 4.0-6.2]. A significantly higher figure of 58.6/100 000 (95% CI 34.7-92.6) was noted for Australian families of Lebanese origin. Clinical awareness of respiratory chain disorders and investigation methods have improved since 1987, but not all affected children would have been recognized as such from the more recent years. The minimum birth prevalence of 6.2/100 000 (95% CI 4.5-8.4) for the 43 patients born between 1991 and 1994 is thought to be a more accurate estimate for respiratory chain disorders presenting in childhood. Combining our data with a previous study on prevalence of adult-onset respiratory chain disorders predicts a minimum birth prevalence of 13.1/100 000 or 1/7634 for respiratory chain disorders with onset at any age.

Dissociations of cerebral cortex, subcortical and cerebral white matter volumes in autistic boys

Abstract: High-functioning autistic and normal school-age boys were compared using a whole-brain morphometric profile that includes both total brain volume and volumes of all major brain regions. We performed MRI-based morphometric analysis on the brains of 17 autistic and 15 control subjects, all male with normal intelligence, aged 7-11 years. Clinical neuroradiologists judged the brains of all subjects to be clinically normal. The entire brain was segmented into cerebrum, cerebellum, brainstem and ventricles. The cerebrum was subdivided into cerebral cortex, cerebral white matter, hippocampus-amygdala, caudate nucleus, globus pallidus plus putamen, and diencephalon (thalamus plus ventral diencephalon). Volumes were derived for each region and compared between groups both before and after adjustment for variation in total brain volume. Factor analysis was then used to group brain regions based on their intercorrelations. Volumes were significantly different between groups overall; and diencephalon, cerebral white matter, cerebellum and globus pallidus-putamen were significantly larger in the autistic group. Brain volumes were not significantly different overall after adjustment for total brain size, but this analysis approached significance and effect sizes and univariate comparisons remained notable for three regions, although not all in the same direction: cerebral white matter showed a trend towards being disproportionately larger in autistic boys, while cerebral cortex and hippocampus-amygdala showed trends toward being disproportionately smaller. Factor analysis of all brain region volumes yielded three factors, with central white matter grouping alone, and with cerebral cortex and hippocampus-amygdala grouping separately from other grey matter regions. This morphometric profile of the autistic brain suggests that there is an overall increase in brain volumes compared with controls. Additionally, results suggest that there may be differential effects driving white matter to be larger and cerebral cortex and hippocampus-amygdala to be relatively smaller in the autistic than in the typically developing brain. The cause of this apparent dissociation of cerebral cortical regions from subcortical regions and of cortical white from grey matter is unknown, and merits further investigation.

Pneumococcal meningitis in adults: spectrum of complications and prognostic factors in a series of 87 cases.

Abstract: Studies on the incidence and spectrum of complications and prognostic factors in adults with pneumococcal meningitis are scarce. Therefore, we analysed 87 consecutive cases who were treated in our department between 1984 and 2002. Meningitis‐associated intracranial complications developed in 74.7% and systemic complications in 37.9% of cases. Diffuse brain oedema (28.7%) and hydrocephalus (16.1%) developed more frequently than previously reported. The incidences of arterial (21.8%) and venous (9.2%) cerebrovascular complications were also very high. Furthermore, 9.2% of cases developed spontaneous intracranial haemorrhages (two patients with subarachnoid and two with subarachnoid and intracerebral bleedings, all in association with vasculitis; one subject with intracerebral haemorrhage due to sinus thrombosis; and three cases with intracerebral bleedings of unknown aetiology). Other new findings were the incidence of acute spinal cord dysfunction due to myelitis (2.3%) and that of hearing loss (19.5% of all patients and 25.8% of survivors). The in‐hospital mortality was 24.1%. Only 48.3% of the patients had a good outcome at discharge [Glasgow Outcome Scale Score (GOS) = 5]. Outcome did not change during the study period, as mortality and GOS were similar for patients treated between 1984 and 1992 and for those treated between 1993 and 2002. Factors associated with a bad outcome (GOS ≤ 4) were chronic debilitating diseases, low Glasgow Coma Scale Score and focal neurological deficits on admission, low CSF leucocyte counts, pneumonia, bacteraemia and meningitis‐associated intracranial and systemic complications. Low CSF leucocyte counts were also associated with the development of meningitis‐associated intracranial complications. Age ≥60 years was associated with a higher mortality (36.7 versus 17.5%), but the GOS of the survivors was comparable to that of the surviving younger patients. The causes of death were mostly systemic complications in the elderly and cerebral complications in the younger patients. A haematogenous pathogenesis seemed likely in asplenic patients, while contiguous spread from sinusitis or otitis was the major cause of meningitis in non‐asplenic individuals. Furthermore, asplenic patients had a raised incidence of meningitis‐associated intracranial complications, but their outcome was similar to that of non‐asplenic subjects. The morbidity and mortality of pneumococcal meningitis in adults are still devastating. We report higher incidences (diffuse brain swelling, hydrocephalus, cerebrovascular complications) or new incidences (myelitis, hearing loss, subarachnoid bleeding) of intracranial complications. Our detailed analysis of prognostic factors may help clinicians to identify patients at risk and may also be helpful in the design of clinical trials.

Axonal damage: a key predictor of outcome in human CNS diseases.

Abstract: Axonal damage has recently been recognized to be a key predictor of outcome in a number of diverse human CNS diseases, including head and spinal cord trauma, metabolic encephalopathies, multiple sclerosis and other white-matter diseases (acute haemorrhagic leucoencephalitis, leucodystrophies and central pontine myelinolysis), infections [malaria, acquired immunodeficiency syndrome (AIDS) and infection with human lymphotropic virus type 1 (HTLV-I) causing HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP)] and subcortical ischaemic damage. The evidence for axonal damage and, where available, its correlation with neurological outcome in each of these conditions is reviewed. We consider the possible pathogenetic mechanisms involved and how increasing understanding of these may lead to more effective therapeutic or preventive interventions.

Patterning of globus pallidus local field potentials differs between Parkinson’s disease and dystonia

Abstract: Here we test the hypothesis that there are distinct temporal patterns of synchronized neuronal activity in the pallidum that characterize untreated and treated parkinsonism and dystonia. To this end we recorded local field potentials (LFPs) from the caudal and rostral contact pairs of macroelectrodes implanted into the pallidum of patients for the treatment of Parkinson's disease (12 cases recorded on and off medication, 17 macroelectrodes) and dystonia (10 cases, 19 macroelectrodes). Percentage LFP power in the 11-30 Hz band was decreased and that in the 4-10 Hz band increased across both contact pairs in treated Parkinson's disease compared with untreated Parkinson's disease. Dystonic patients had even less 11-30 Hz power and greater 4-10 Hz power compared with untreated or treated Parkinson's disease patients. The change in the 4-10 Hz band in patients with dystonia was particularly manifest in the more rostral contact pair, presumed to be within or bridging the globus pallidus externus. We conclude that untreated and treated Parkinson's disease and dystonia are characterized by different spatiotemporal patterns of activity in the human pallidum.