Showing papers in "Brain in 1997"

The columnar organization of the neocortex.

Abstract: The modular organization of nervous systems is a widely documented principle of design for both vertebrate and invertebrate brains of which the columnar organization of the neocortex is an example. The classical cytoarchitectural areas of the neocortex are composed of smaller units, local neural circuits repeated iteratively within each area. Modules may vary in cell type and number, in internal and external connectivity, and in mode of neuronal processing between different large entities; within any single large entity they have a basic similarity of internal design and operation. Modules are most commonly grouped into entities by sets of dominating external connections. This unifying factor is most obvious for the heterotypical sensory and motor areas of the neocortex. Columnar defining factors in homotypical areas are generated, in part, within the cortex itself. The set of all modules composing such an entity may be fractionated into different modular subsets by different extrinsic connections. Linkages between them and subsets in other large entities form distributed systems. The neighborhood relations between connected subsets of modules in different entities result in nested distributed systems that serve distributed functions. A cortical area defined in classical cytoarchitectural terms may belong to more than one and sometimes to several distributed systems. Columns in cytoarchitectural areas located at some distance from one another, but with some common properties, may be linked by long-range, intracortical connections.

Localization of the motor hand area to a knob on the precentral gyrus. A new landmark.

Abstract: Using functional magnetic resonance imaging (fMRI) we have evaluated the anatomical location of the motor hand area. The segment of the precentral gyrus that most often contained motor hand function was a knob-like structure, that is shaped like an omega or epsilon in the axial plane and like a hook in the sagittal plane. On the cortical surface of cadaver specimens this precentral knob corresponded precisely to the characteristic 'middle knee' of the central sulcus that has been described by various anatomists in the last century. We were then able to show that this knob is a reliable landmark for identifying the precentral gyrus directly. We therefore conclude that neural elements involved in motor hand function are located in a characteristic 'precentral knob' which is a reliable landmark for identifying the precentral gyrus under normal and pathological conditions. It faces and forms the 'middle knee' of the central sulcus, is located just at the cross point between the precentral sulcus and the central sulcus, and is therefore also visible on the cortical surface.

Axonal damage in acute multiple sclerosis lesions.

Abstract: One of the histological hallmarks of early multiple sclerosis lesions is primary demyelination, with myelin destruction and relative sparing of axons. On the other hand, it is widely accepted that axonal loss occurs in, and is responsible for, the permanent disability characterizing the later chronic progressive stage of the disease. In this study, we have used an antibody against amyloid precursor protein, known to be a sensitive marker of axonal damage in a number of other contexts, in immunocytochemical experiments on paraffin embedded multiple sclerosis lesions of varying ages in order to see at which stage of the disease axonal damage, in addition to demyelination, occurs and may thus contribute to the development of disability in patients. The results show the expression of amyloid precursor protein in damaged axons within acute multiple sclerosis lesions, and in the active borders of less acute lesions. This observation may have implications for the design and timing of therapeutic intervention, one of the most important aims of which must be the reduction of permanent disability.

Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis.

Abstract: We compared MRI criteria used to predict conversion of suspected multiple sclerosis to clinically definite multiple sclerosis. Seventy-four patients with clinically isolated neurological symptoms suggestive of multiple sclerosis were studied with MRI. Logistic regression analysis was used to remove redundant information, and a diagnostic model was built after each MRI parameter was dichotomized according to maximum accuracy using receiver operating characteristic analysis. Clinically definite multiple sclerosis developed in 33 patients (prevalence 45%). The optimum cut-off point (number of lesions) was one for most MRI criteria (including gadolinium-enhancement and juxta-cortical lesions), but three for periventricular lesions, and nine for the total number of T2-lesions. Only gadolinium-enhancement and juxta-cortical lesions provided independent information. A final model which, in addition, included infratentorial and periventricular lesions, had an accuracy of 80%, and having more abnormal criteria, predicted conversion to clinically definite multiple sclerosis strongly. The model performed better than the criteria of Paty et al. (Neurology 1988; 38: 180-5) and of Fazekas et al. (Neurology 1988; 38: 1822-5). We concluded that a four-parameter dichotomized MRI model including gadolinium-enhancement, juxtacortical, infratentorial and periventricular lesions best predicts conversion to clinically definite multiple sclerosis.

Regional cerebral blood flow throughout the sleep-wake cycle. An H2(15)O PET study

Abstract: To assess dynamic changes in brain function throughout the sleep-wake cycle, CBF was measured with H2(15)O and PET in 37 normal male volunteers: (i) while awake prior to sleep onset; (ii) during Stage 3-4 sleep, i.e. slow wave sleep (SWS); (iii) during rapid eye movement (REM) sleep; and (iv) upon waking following recovery sleep. Subjects were monitored polysomnographically and PET images were acquired throughout the course of a single night. Stage-specific contrasts were performed using statistical parametric mapping. Data were analysed in repeated measures fashion, examining within-subject differences between stages [pre-sleep wakefulness-SWS (n = 20 subjects); SWS-post-sleep wakefulness (n = 14); SWS-REM sleep (n = 7); pre-sleep wakefulness-REM sleep (n = 8); REM sleep-post-sleep wakefulness (n = 7); pre-sleep wakefulness-post-sleep wakefulness (n = 20)]. State dependent changes in the activity of centrencephalic regions, including the brainstem, thalamus and basal forebrain (profound deactivations during SWS and reactivations during REM sleep) are consistent with the idea that these areas are constituents of brain systems which mediate arousal. Shifts in the level of activity of the striatum suggested that the basal ganglia might be more integrally involved in the orchestration of the sleep-wake cycle than previously thought. State-dependent changes in the activity of limbic and paralimbic areas, including the insula, cingulate and mesial temporal cortices, paralleled those observed in centrencephalic structures during both REM sleep and SWS. A functional dissociation between activity in higher order, heteromodal association cortices in the frontal and parietal lobes and unimodal sensory areas of the occipital and temporal lobes appeared to be characteristic of both SWS and REM sleep. SWS was associated with selective deactivation of the heteromodal association areas, while activity in primary and secondary sensory cortices was preserved. SWS may not, as previously thought, represent a generalized decrease in neuronal activity. On the other hand, REM sleep was characterized by selective activation of certain post-rolandic sensory cortices, while activity in the frontoparietal association cortices remained depressed. REM sleep may be characterized by activation of widespread areas of the brain, including the centrencephalic, paralimbic and unimodal sensory regions, with the specific exclusion of areas which normally participate in the highest order analysis and integration of neural information. Deactivation of the heteromodal association areas (the orbital, dorsolateral prefrontal and inferior parietal cortices) constitutes the single feature common to both non-REM and REM sleep states, and may be a defining characteristic of sleep itself. The stages of sleep could also be distinguished by characteristic differences in the relationships between the basal ganglia, thalamic nuclei and neocortical regions of interest.

Brain activity during observation of actions. Influence of action content and subject's strategy.

Abstract: PET was used to map brain regions that are associated with the observation of meaningful and meaningless hand actions. Subjects were scanned under four conditions which consisted of visually presented actions. In each of the four experimental conditions, they were instructed to watch the actions with one of two aims: to be able to recognize or to imitate them later. We found that differences in the meaning of the action, irrespective of the strategy used during observation, lead to different patterns of brain activity and clear left/right asymmetries. Meaningful actions strongly engaged the left hemisphere in frontal and temporal regions while meaningless actions involved mainly the right occipitoparietal pathway. Observing with the intent to recognize activated memory-encoding structures. In contrast, observation with the intent to imitate was associated with activation in the regions involved in the planning and in the generation of actions. Thus, the pattern of brain activation during observation of actions is dependent both on the nature of the required executive processing and the type of the extrinsic properties of the action presented.

Functional localization of the system for visuospatial attention using positron emission tomography.

Abstract: PET was used to image the neural system underlying visuospatial attention. Analysis of data at both the group and individual-subject level provided anatomical resolution superior to that described to date. Six right-handed male subjects were selected from a pilot behavioural study in which behavioural responses and eye movements were recorded. The attention tasks involved covert shifts of attention, where peripheral cues indicated the location of subsequent target stimuli to be discriminated. One attention condition emphasized reflexive aspects of spatial orientation, while the other required controlled shifts of attention. PET activations agreed closely with the cortical regions recently proposed to form the core of a neural network for spatial attention. The two attention tasks evoked largely overlapping patterns of neural activation, supporting the existence of a general neural system for visuospatial attention with regional functional specialization. Specifically, neocortical activations were observed in the right anterior cingulate gyrus (Brodmann area 24), in the intraparietal sulcus of right posterior parietal cortex, and in the mesial and lateral premotor cortices (Brodmann area 6).

Generalized epilepsy with febrile seizures plus: A genetic disorder with heterogeneous clinical phenotypes

Abstract: The clinical and genetic relationships of febrile seizures and the generalized epilepsies are poorly understood. We ascertained a family with genealogical information in 2000 individuals where there was an unusual concentration of individuals with febrile seizures and generalized epilepsy in one part of the pedigree. We first clarified complex consanguineous relationships in earlier generations and then systematically studied the epilepsy phenotypes in affected individuals. In one branch (core family) 25 individuals over four generations were affected. The commonest phenotype, denoted as 'febrile seizures plus' (FS+), comprised childhood onset (median 1 year) of multiple febrile seizures, but unlike the typical febrile convulsion syndrome, attacks with fever continued beyond 6 years, or afebrile seizures occurred. Seizures usually ceased by mid childhood (median 11 years). Other phenotypes included FS+ and absences, FS+ and myoclonic seizures, FS+ and atonic seizures, and the most severely affected individual had myoclonic-astatic epilepsy (MAE). The pattern of inheritance was autosomal dominant. The large variation in generalized epilepsy phenotypes was not explained by acquired factors. Analysis of this large family and critical review of the literature led to the concept of a genetic epilepsy syndrome termed generalized epilepsy with febrile seizures plus (GEFS+). GEFS+ has a spectrum of phenotypes including febrile seizures, FS+ and the less common MAE. Recognition of GEFS+ explains the epilepsy phenotypes of previously poorly understood benign childhood generalized epilepsies. In individual patients the inherited nature of GEFS+ may be overlooked. Molecular genetic study of such large families should allow identification of genes relevant to febrile seizures and generalized epilepsies.

A review of paroxysmal hemicranias, SUNCT syndrome and other short-lasting headaches with autonomic feature, including new cases.

Abstract: The short-lasting primary headache syndromes may be conveniently divided into those exhibiting marked autonomic activation and those without autonomic activation. The former group comprise chronic and episodic paroxysmal hemicrania, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT syndrome) and cluster headache. These headache syndromes are compared with other short-lasting headache disorders, such as hypnic headache, and persistent headache with milder autonomic features such as hemicrania continua. Cluster headache is included with the shorter-lasting headaches to attempt a nosological analysis of these syndromes. The paroxysmal hemicranias are characterized by frequent short-lasting attacks of unilateral pain usually in the orbital, supraorbital or temporal region that typically last minutes. The attack frequency usually ranges from 5 to 40 attacks per day. The pain is severe and associated with autonomic symptoms such as conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, ptosis or eyelid oedema. Almost all reported cases respond to treatment with indomethacin, but respond poorly to other treatments including other nonsteroidal anti-inflammatory drugs. A recent case study demonstrated the release of both trigeminal and parasympathetic neuropeptides during a bout of pain in the same pattern previously described in cluster headache. The SUNCT syndrome is a distinctive rare condition characterized by less severe pain but marked autonomic activation during attacks. Consistent with previous reports, the present case of SUNCT syndrome was intractable to therapy. The similarites of these syndromes suggests a considerable shared pathophysiology. It is suggested that the syndromes are sufficiently well established for inclusion in the International Headache Society Classification system and that trigeminal-autonomic cephalalgias should be classified as a group together. A proposed re-classification is presented.

The structural components of music perception. A functional anatomical study.

Abstract: This work explores the cerebral structures involved in the appreciation of music. We studied six young healthy subjects (right handed, French, without musical talent), using a high resolution PET device (CTI 953B) and 15O-labelled water. In three tasks, we studied the effects of selective attention to pitch, timbre and rhythm; a final task studied semantic familiarity with tunes (considered as divided attention for pitch and rhythm). These four tasks were performed on the same material (a tape consisting of 30 randomly arranged sequences of notes). We selected a paradigm, without a reference task, to compare the activations produced by attention to different parameters of the same stimulus. We expected that the activations recorded during each task would differ according to the differences in cognitive operations. We found activations preferentially in the left hemisphere for familiarity, pitch tasks and rhythm, and in the right hemisphere for the timbre task. The familiarity task activated the left inferior frontal gyrus, Brodmann area (BA) 47, and superior temporal gyrus (in its anterior part, BA 22). These activations presumably represent lexico-semantic access to melodic representations. In the pitch task, activations were observed in the left cuneus/precuneus (BA 18/19). These results were unexpected and we interpret them as reflecting a visual mental imagery strategy employed to carry out this task. The rhythm task activated left inferior Broca's area (BA 44/6), with extention into the neighbouring insula, suggesting a role for this cerebral region in the processing of sequential sounds.

Primary progressive multiple sclerosis.

Abstract: Patients with multiple sclerosis who develop progressive disability from onset without relapses or remissions pose difficulties in diagnosis, monitoring of disease activity and treatment. There is a need to define the diagnostic criteria for this group more precisely and, in particular, to describe a comprehensive battery of investigations to exclude other conditions. The mechanisms underlying the development of disability and the role of MRI in monitoring disease activity in this clinical subgroup require elucidation, particularly in view of the lack of change on conventional imaging in the presence of continuing clinical deterioration. The prognosis is poor and there are currently no treatment trials for this form of the disease.

Imaging and epilepsy.

Abstract: MRI has been applied to the investigation of epilepsy for 12 years. The principle role of MRI is in the definition of structural abnormalities that underly seizure disorders. Hippocampal sclerosis may be reliably identified, quantitative studies are useful for research and, in equivocal cases, for clinical purposes. A range of malformations of cortical development (MCD) may be determined. In patients with refractory partial seizures who are candidates for surgical treatment, a relevant abnormality is identifiable using MRI in 85%, it is likely that subtle MCD or gliosis accounts for the majority of the remainder. The proportion of cryptogenic cases will decrease with improvements in MRI hardware, signal acquisition techniques and post-processing methodologies. Functional MRI is used to identify the cerebral areas that are responsible for specific cognitive processes, and is of importance in planning resections close to eloquent cortical areas. Magnetic resonance spectroscopy (MRS) provides a means of investigating cerebral metabolites and some neurotransmitters, non-invasively. The concentrations of N-acetyl-aspartate (NAA), creatine and choline-containing compounds may be estimated using proton MRS. Reduction of the ratio of NAA/(creatine+choline) is a feature of cerebral regions that include epileptic foci. Cerebral concentrations of GABA and glutamate, and the effects of antiepileptic drugs on these, may be estimated. Concentrations of high energy phosphate compounds, inorganic phosphate and pH may be assessed using 31P-MRS. In general, epileptic foci are associated with an increase in pH, increased inorganic phosphate and decreased phosphate monoesters. Carbon-13 spectroscopy promises to be a useful method for investigating cerebral metabolism in vivo. PET may provide data on regional cerebral blood flow (rCBF), glucose metabolism and the binding of specific ligands to receptors. Correlation of functional and structural imaging data is necessary for adequate interpretation. The hallmark of an epileptic focus is an area of reduced glucose metabolism, identified using [18F]fluorodeoxyglucose (18FDG), that is commonly more extensive than the underlying anatomical abnormality. The clinical role of 18FDG-PET requires re-evaluation in the light of the advances in structural imaging with MRI. Specific ligands are used to investigate specific receptors. Benzodiazepine and opioid receptors have been studied most. Reduced benzodiazepine receptor binding is commonly seen at an epileptic focus, in a more restricted distribution than an area of hypometabolism. Focal increases and decreases in benzodiazepine receptor binding have been demonstrated in MCD in areas that appear normal on MRI, indicating the widespread nature of the abnormalities. It has been found that mu-opioid receptors are increased in temporal neocortex overlying mesial temporal epileptic foci. Dynamic studies of ligand-receptor binding are possible using PET, for example the release of cerebral endogenous opioids has been implied at the time of serial absences. The main use of single photon emission computed tomography (SPECT) is to produce images reflecting rCBF. Interictal studies alone are not reliable. A strength of SPECT is the ability to obtain images related to rCBF at the time of seizures. Concomitant video-EEG recording is necessary. Ictal scans need to be considered in comparison with an interictal scan and an MRI. Interpretation must be cautious, but may yield data that is useful in the investigation of patients for possible surgical treatment.

A PET study on brain control of micturition in humans.

Abstract: Although the brain plays a crucial role in the control of micturition, little is known about the structures involved. Identification of these areas is important, because their dysfunction is though to cause urge incontinence, a major problem in the elderly. In the cat, three areas in the brainstem and diencephalon are specifically implicated in the control of micturition: the dorsomedial pontine tegmentum, the periaqueductal grey, and the preoptic area of the hypothalamus. PET scans were used to test whether these areas are also involved in human micturition. Seventeen right-handed male volunteers were scanned during the following four conditions: (i) 15 min prior to micturition during urine withholding: (ii) during micturition; (iii) 15 min after micturition; (iv) 30 min after micturition. Ten of the 17 volunteers were able to micturate during scanning. micuturition was associated with increased blood flow in the right dorsomedial pontine tegmentum, the periaqueductal grey, the hypothalamus and the right inferior frontal gyrus. Decreased blood flow was found in the right anterior cingulate gyrus when urine was withheld. The other seven volunteers were not able to micturate during scanning, although they had a full bladder and tried vigorously to do so. In this group, during these unsuccessful attempts to micturate, increased blood flow was found in the right ventral pontine tegmentum, which corresponds with the hypothesis, formulated from results in cats, that this area controls the motor neurons of the pelvic floor. Increased blood flow was also found in the right inferior frontal gyrus during unsuccessful attempts at micturition, and decreased blood flow in the right anterior cingulate gyrus was found during the withholding of urine. The results suggest that, as that of the cat, the human brainstem contains specific nuclei responsible for the control of micturition, and that the cortical and pontine micturition sites are predominantly on the right side.

Attention and stimulus characteristics determine the locus of motor–sequence encoding a PET study.

Abstract: PET revealed the effects of stimulus characteristics on the neural substrate of motor learning. Right-handed subjects performed a serial reaction time task with colour-coded stimuli to eliminate the potential for learned eye-movements. The task was performed with the right hand under two different conditions. In one condition, subjects simultaneously performed a distractor task. Although they did show behavioural evidence of learning, they were not explicitly aware of the stimulus-response sequence. In the second condition, there was no distractor task, and seven out of the 11 subjects then became explicitly aware of the stimulus sequence. Metabolic correlates of learning were distinct in the two conditions. When learning was implicit under dual-task conditions, learning-related changes were observed in left motor and supplementary motor cortex as well as in the putamen. These regions are similar to those observed in a previous study in which the stimuli were cued by spatial position. Under single-task conditions, metabolic changes were found in the right prefrontal cortex and premotor cortex, as well as in the temporal lobe. A similar shift to the right hemisphere was observed in the spatial study during single-task learning. However, explicit learning of the task with colour stimuli activated more ventral regions. The areas supporting motor-sequence learning are contingent on both stimulus properties and attentional constraints.

Frontal-striatal cognitive deficits in patients with chronic schizophrenia.

Abstract: Spatial working memory and planning abilities were assessed in 36 hospitalized patients with chronic schizophrenia, using the computerized Cambridge Neuropsychological Test Automated Battery (CANTAB), and compared with those of normal subjects and patients with neurological disorders (frontal lobe lesions; temporal lobe and amygdalohippocampal lesions; Parkinson's disease), matched for age, sex and National Adult Reading Test IQ. The patients in the group with temporal lobe lesions were unimpaired in their performance on these tasks. Patients with schizophrenia were impaired on visuo-spatial memory span compared with all the other groups, while severity of Parkinson's disease was correlated with the degree of impairment on this task. The patients with schizophrenia and those with frontal lobe lesions were impaired on a 'spatial working memory' task, with increased 'between-search errors'. Patients with Parkinson's disease performed this task poorly compared with the younger control subjects. Patients with schizophrenia were unable to develop a systematic strategy to complete this task, relying instead on a limited visuo-spatial memory span. Higher level planning ability was investigated using the CANTAB 'Tower of London'. All groups were equally able to complete the task. However, the groups of patients with schizophrenia and frontal lobe lesions made fewer perfect solutions and required more moves for completion. Movement times were significantly slower in the schizophrenia group, suggesting impairment in the sensorimotor requirements of the task. The patients with schizophrenia were not impaired in their 'initial thinking' (planning) latencies, but had significantly prolonged 'subsequent thinking' (execution) latencies. This pattern resembled that of the group with frontal lobe lesions and contrasted with the prolonged 'initial thinking' time seen in Parkinson's disease. The results of this study are indicative of an overall deficit of executive functioning in schizophrenia, even greater than that seen in patients with frontal lobe lesions. However, the pattern of results in schizophrenia resembled that seen in patients with lesions of the frontal lobe or with basal ganglia dysfunction, providing support for the notion of a disturbance of frontostriatal circuits in schizophrenia. Our findings also indicate that there is a loss of the normal relationships between different domains of executive function in schizophrenia, with implications for impaired functional connectivity between different regions of the neocortex.

A PET study of voluntary movement in schizophrenic patients experiencing passivity phenomena (delusions of alien control).

Abstract: Schizophrenic patients experiencing passivity phenomena believe their thoughts and actions to be those of external, or alien, entities. We wished to test the hypothesis that voluntary motor action in such patients would be associated with aberrant patterns of activation within the cerebral motor system. We used H2(15)O PET to study patients while they performed paced joystick movements on two occasions 4-6 weeks apart. During the first scan passivity symptoms were maximal, while by the second scan these symptoms had significantly improved in five of the seven patients. Two control groups were also scanned on two occasions: deluded schizophrenic patients without passivity phenomena and normal subjects. In normal subjects, performance of freely selected joystick movements with the right hand, compared with rest, revealed relative activation of prefrontal, premotor, motor and parietal cortical regions. Schizophrenic patients with passivity showed hyperactivation of parietal and cingulate cortices. This hyperactivation remitted in those subjects in whom passivity decreased over time. This reversible hyperactivity was not a feature of schizophrenics without passivity. Given that these hyperactive cerebral regions subserve attention to internal and external bodily space, and the attribution of significance to sensory information, they provide a plausible anatomical substrate for the misattribution of internally generated acts to external entities: the cardinal feature of delusions of passivity (alien control).

Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy.

Abstract: The occasion of the presentation of the eighth Gordon Holmes Lecture left me feeling both honoured and awed, as a result of my review of the Selected Papers of Gordon Holmes (Phillips CG: Selected Papers of Gordon Holmes, compiled and edited for the Guarantors of Brain. Oxford University Press, 1979), kindly presented to me by the sponsors of the meeting. This volume lists 174 publications produced over a 55-year period, and contains reprints of contributions to neuroanatomy, neuropathology, and to disorders that affected the adrenal cortex, the spinal cord, the cerebellum and the cerebral cortex. Yet I also feel a sense of sadness; the invitation to present the lecture came from the late Anita Harding who, such a short time before her illness, gave me personal guidance and encouragement. In this lecture I endeavour to follow the example of Gordon Holmes, namely the stepwise analysis of a clinical problem, first by observation of the patient, followed by the application of techniques that can clarify it, leading to new knowledge not only about the specific disorder, but also about the nervous system and human biology in general and, it is to be hoped, to more effective therapy.

Phonological and orthographic components of word recognition. A PET-rCBF study.

Abstract: Pronunciation (of irregular/inconsistent words and of pseudowords) and lexical decision-making tasks were used with 15O PET to examine the neural correlates of phonological and orthographic processing in 14 healthy right-handed men (aged 18-40 years). Relative to a visual-fixation control task, all four experimental tasks elicited a left-lateralized stream of activation involving the lingual and fusiform gyri, perirolandic cortex, thalamus and anterior cingulate. Both pronunciation tasks activated the left superior temporal gyrus, with significantly greater activation seen there during phonological (pseudoword) than during orthographic (real word) pronunciation. The left inferior frontal cortex was activated by both decision-making tasks; more intense and widespread activation was seen there during phonological, than during orthographic, decision making, with the activation during phonological decision-making extending into the left insula. Correlations of reference voxels in the left superior temporal gyrus and left inferior frontal region with the rest of the brain were highly similar for the phonological and orthographic versions of each task type. These results are consistent with connectionist models of reading, which hypothesize that both real words and pseudowords are processed within a common neural network.

Reorganization of motor output in the non-affected hemisphere after stroke.

Abstract: Motor evoked responses to focal transcranial magnetic stimulation were investigated over the unaffected hemisphere in 15 patients with hemiparesis after ischaemic stroke and compared with data from normal control subjects. Whereas responses to muscles ipsilateral to the stimulated hemisphere could only be elicited at maximal intensities in two out of 12 normal control subjects, such ipsilateral responses were recorded after stimulation of the unaffected hemisphere in patients with poor recovery after stroke at significantly lower thresholds, but not in patients with good recovery. These responses occurred with a somewhat longer (on average 6 ms) latency than the typical contralateral response. The duration of the silent period ipsilateral to stimulation of the unaffected hemisphere was longer than in control subjects. Also the contralateral threshold for the unaffected hemisphere was elevated in comparison with the control group. In one patient, who developed mirror movements after stroke, the ipsilateral threshold was exceptionally low and the latency of the ipsilateral response identical to that seen contralaterally. It is concluded that the motor outputs in the unaffected hemisphere are significantly changed after stroke, including the unmasking of ipsilateral corticospinal projections. However, these pathways seem to be of little significance for recovery, as the existence of these responses was not correlated with clinical improvement. The unaffected hemisphere after stroke shows plastic changes in motor output organization after a contralateral lesion.

Blindsight in man and monkey.

Abstract: In man and monkey, absolute cortical blindness is caused by destruction of the optic radiations and/or the primary visual cortex. It is characterized by an absence of any conscious vision, but stimuli presented inside its borders may nevertheless be processed. This unconscious vision includes neuroendocrine, reflexive, indirect and forced-choice responses which are mediated by the visual subsystems that escape the direct cerebral damage and the Ensuring degeneration. While extrastriate cortical areas participate in the mediation of the forced-choice responses, a concomitant striate cortical activation does not seem to be necessary for blindsight. Whether the loss of phenomenal vision is a necessary consequence of striate cortical destruction and whether this structure is indispensable for conscious sight are much debated questions which need to be tackled experimentally.

The position and topography of the human colour centre as revealed by functional magnetic resonance imaging.

Abstract: We used a colour Mondrian--an abstract scene with no recognizable objects--and its achromatic version to image the change in blood oxygenation in the brains of 12 human subjects, with the aim of learning more about the position and variability of the colour centre in the human brain. The results showed a consistent association of colour stimulation with activation of an area that is distinct from the primary visual areas, and lies in the ventral occipitotemporal cortex; we refer to it as human V4. The position of human V4, as defined on functional grounds, varies between individuals in absolute terms but is invariably found on the lateral aspect of the collateral sulcus on the fusiform gyrus. There was no indication of lingual gyral activation. In further studies designed to reveal the topographic map within V4, we stimulated the superior and inferior visual fields separately, using the same stimuli. We found that human V4 contains a representation of both the superior and inferior visual fields. In addition, there appears to be retinotopic organization of V4 with the superior visual field being represented more medially on the fusiform gyrus and the inferior field more laterally, the two areas abutting on one another. We find no evidence that suggests the existence of a separate representation of the inferior hemifield for colour in more dorsolateral regions of the occipital lobe.

Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives.

Abstract: Based on exciting results in animal models, a number of novel immunotherapies employing biotechnological products, rather than conventional immunosuppressants, are being developed for the treatment of multiple sclerosis. The first part of this article is a review of some fundamental concepts of immunology and offers a hypothetical scenario for the immunopathogenesis of multiple sclerosis. The second part provides a critical overview of various immunotherapies relying on modern biotechnology. For each approach, the underlying immunological principles, experimental and clinical evidence, and foreseeable problems are separately addressed. Thus, it is hoped that this article serves a dual purpose, namely to provide an update on recent advances in immunology, and to serve as a useful source of reference to immunotherapies holding promise for future treatment of multiple sclerosis.

Evidence for lateral premotor and parietal overactivity in Parkinson's disease during sequential and bimanual movements. A PET study.

Abstract: Patients with Parkinson's disease have great difficulty in performing sequential and bimanual movements. We used H2(15)O PET to study the regional cerebral blood flow associated with performance of sequential finger movements made unimanually and bimanually in a group of Parkinson's disease patients and a group of control volunteers. In controls, sequential finger movements led to activation of the contralateral motor cortex and inferior parietal cortex (Brodmann area 40), the lateral premotor cortex and bilateral supplementary motor area. No prefrontal activation was seen. Sequential finger movements in the Parkinson's disease group were associated with a similar pattern of activation but there was relative impairment of activation in the mesial frontal and prefrontal areas. A novel finding was the presence of relative overactivity in the lateral premotor and inferolateral parietal regions. We conclude that in Parkinson's disease there is a switch from the use of striato-mesial frontal to parietal-lateral premotor circuits in order to facilitate performance of complex finger movements.

Molecular pathology of MELAS and MERRF. The relationship between mutation load and clinical phenotypes.

Abstract: Many patients with inherited mitochondrial encephalopathies have one of two pathogenic mutations of mitochondrial DNA (mtDNA): A3243G or A8344G. Individuals who harbour these mutations carry both mutant and wild-type alleles within each cell (heteroplasmy). Despite clear evidence of a direct relationship between the level of mutation and mitochondrial respiratory chain function in vitro, it has been more difficult to demonstrate a clear correlation between clinical phenotype and the level of mutant mtDNA in vivo. To address this issue, we identified 245 individuals who carry either the A3243G or A8344G mutations, and studied the relationship between the incidence of specific clinical features and the level of mutant mtDNA in blood (for A3243G, n = 73; for A8344G, n = 25) and/or skeletal muscle (for A3234G, n = 111; for A8344G, n = 55). Within this study group, the frequency of key clinical features was significantly different for individuals harbouring the A3243G and A8344G mutations. For both mutations, there was a correlation between the frequency of the more common clinical features and the level of mutant mtDNA in muscle. In contrast, we did not observe a correlation between the frequency of clinical features and the level of mutant mtDNA in blood. Therefore, measurement of the level of the A3243G and A8344G mutations in muscle will allow the identification of individuals who are at risk of developing specific complications, thus improving the prognostic advice that can be given to patients and family members who carry these mutations.

Genetic variability of human brain size and cortical gyral patterns.

Abstract: The development of the primate brain is determined by an interaction of genetic programmes and environmental events. We examined quantitatively the contribution of each of these factors to adult human brain hemisphere volume and global cortical gyral patterns by comparing 3-D MRI renderings of brains of 10 pairs of monozygotic (MZ) and nine pairs of same-sex dizygotic (DZ) twins. Brain volume was highly correlated in MZ pairs [unbiased intraclass correlation coefficient, ICC(U) = 0.95, P < 0.00001], but not in DZ pairs [ICC(U) = 0.35, P = 0.09]. Structural equation modelling indicated a 94% heritability of brain volume. Gyral patterns appeared visually more similar in MZ than in DZ pairs. This was confirmed statistically by a cross-correlation analysis of rendered images of lateral and mesial cortical surfaces. MZ twins exhibited significantly greater similarity than did DZ twins in comparisons of gyral patterns; DZ twins were not more alike than unrelated pairings. Ipsilateral hemispheres were significantly more alike than contralateral hemispheres within MZ pairs, but not within DZ pairs. Contralateral hemispheres within an individual were more alike than contralateral hemispheres between twins in the DZ pairs, but not in the MZ pairs. Heritability for gyral-sulcal patterns, as reflected in the cross-correlation data, was low and ill defined. These results indicate that human cerebral size is determined almost entirely by genetic factors and that overall cortical gyral patterns, though significantly affected by genes, are determined primarily by nongenetic factors.

The right brain hemisphere is dominant in human infants.

Abstract: The development of functional brain asymmetry during childhood is confirmed by changes in cerebral blood flow measured at rest using dynamic single photon emission computed tomography. Between 1 and 3 years of age, the blood flow shows a right hemispheric predominance, mainly due to the activity in the posterior associative area. Asymmetry shifts to the left after 3 years. The subsequent time course of changes appear to follow the emergence of functions localized initially on the right, but later on the left hemisphere (i.e. visuospatial and later language abilities). These findings support the hypothesis that, in man, the right hemisphere develops its functions earlier than the left.

Neural mechanisms involved in the processing of global and local aspects of hierarchically organized visual stimuli.

Abstract: We investigated the functional anatomy involved in sustaining or switching visual attention between different perceptual levels, using functional imaging measures of neural activity. Two experiments were carried out using hierarchically organized letters (i.e. large letters made out of small letters). In a divided-attention task, subjects were required to switch attention between local and global levels. The number of successive stimuli for which subjects had to sustain attention to either the global or local level co-varied significantly with temporal-parietal activations bilaterally. Other activations were also observed in the right orbitofrontal cortex, the right dorsolateral prefrontal cortex, and the right middle temporal gyrus. The number of switches between levels co-varied significantly with activations in the left supplementary motor area and the left medial parietal cortex. In the directed-attention task, subjects were required to attend to either the global or local level of the stimuli throughout all trials; attention to the global aspect resulted in significant activation of the right lingual gyrus while attention to the local aspect significantly activated the left inferior occipital cortex. We suggest that left hemisphere activations with increasing numbers of switches between perceptual levels reflect increased demands on an executive attentional system, while sustained attention to either level activates a predominantly right hemispheric network involving temporal-parietal and dorsolateral prefrontal regions. Overall, the results provide evidence for relative hemispheric specialization for global and local processing in accordance with previous neuropsychological studies. In addition, the findings demonstrate that early visual processing mechanisms in the prestriate cortex are influenced by an attentional system in temporal-parietal areas.

Altered patterns of cerebral activity during speech and language production in developmental stuttering. An H2(15)O positron emission tomography study.

Abstract: To assess dynamic brain function in adults who had stuttered since childhood, regional cerebral blood flow (rCBF) was measured with H2O and PET during a series of speech and language tasks designed to evoke or attenuate stuttering. Speech samples were acquired simultaneously and quantitatively compared with the PET images. Both hierarchical task contrasts and correlational analyses (rCBF versus weighted measures of dysfluency) were performed. rCBF patterns in stuttering subjects differed markedly during the formulation and expression of language, failing to demonstrate left hemispheric lateralization typically observed in controls; instead, regional responses were either absent, bilateral or lateralized to the right hemisphere. Significant differences were detected between groups when all subjects were fluent-during both language formulation and non-linguistic oral motor tasks-demonstrating that cerebral function may be fundamentally different in persons who stutter, even in the absence of stuttering. Comparison of scans acquired during fluency versus dysfluency-evoking tasks suggested that during the production of stuttered speech, anterior forebrain regions-which play an a role in the regulation of motor function-are disproportionately active in stuttering subjects, while post-rolandic regions-which play a role in perception and decoding of sensory information-are relatively silent. Comparison of scans acquired during these conditions in control subjects, which provide information about the sensorimotor or cognitive features of the language tasks themselves, suggest a mechanism by which fluency-evoking maneuvers might differentially affect activity in these anterior and posterior brain regions and may thus facilitate fluent speech production in individuals who stutter. Both correlational and contrast analyses suggest that right and left hemispheres play distinct and opposing roles in the generation of stuttering symptoms: activation of left hemispheric regions appears to be related to the production of stuttered speech, while activation of right hemispheric regions may represent compensatory processes associated with attenuation of stuttering symptoms.

The temporal variant of frontotemporal dementia.

Abstract: Frontotemporal dementia is a dementia syndrome with diverse clinical characteristics. Based upon clinical parameters and single photon emission computed tomography, we identified 47 frontotemporal dementia subjects. In 10 of these 47 the primary site of brain dysfunction was anterior temporal and orbital-frontal with other frontal regions relatively spared. In this temporal lobe variant (TLV) of frontotemporal dementia, five of the subjects had more severe left-sided, and five had more right-sided, hypoperfusion. The clinical, neuropsychological and neuropsychiatric features of predominantly left-sided (LTLV) and right-sided (RTLV) TLV subjects are discussed and contrasted with more frontal presentations of frontotemporal dementia. In LTLV, aphasia was usually the first and most severe clinical abnormality RTLV patients presented with behavioural disorders characterized by irritability, impulsiveness, bizarre alterations in dress, limited and fixed ideas, decreased facial expression and increased visual alertness. These findings suggest that: (i) frontotemporal dementia is clinically heterogeneous with bitemporal and inferior frontal lobe dysfunction contributing to the clinical presentation; (ii) behavioural disturbance and aphasia are the most prominent features of predominantly temporal subtypes of frontotemporal dementia; (iii) the right and left anterior temporal regions may mediate different behavioural functions. The results of this study suggests that TLV offers a valuable source of information concerning the behavioural disorders seen with combined anterior temporal and inferior frontal lobe dysfunction.

Cerebellum and procedural learning: evidence from focal cerebellar lesions

Abstract: The aim of the present study was to investigate the influence of focal cerebellar lesions on procedural learning. Eight patients with cerebellar lesions and six control subjects were tested in a serial reaction-time task. A four-choice reaction-time task was employed in which the stimuli followed (or not) a sequence repeated 10 times, with the subjects aware (or not) of the item sequence. Learning was manifested by the reduction in response latency over the sequential blocks. Acquisition of declarative knowledge of the sequence was also tested. Reaction times displayed by patients with cerebellar lesions, even though they tended to be longer than those of control subjects in all testing conditions, significantly differed from control subjects only when the stimuli were presented in sequence. The reaction times in sequential trials were still statistically significant when simple motor response times were taken into account. Cerebellar patients were also significantly impaired in detecting and repeating the sequence. On the other hand, when the sequence was learned before testing, motor performances were significantly improved in all subjects. These data indicate that cerebellar lesions induce specific impairment in the procedural learning of a motor sequence and suggest a role of the cerebellar circuitry in detecting and recognizing event sequences.