Brain

Miller, D, H;Grossman, R, I;Reingold, S, C;McFarland, H, F

doi: 10.1093/brain/121.1.3pmid: 9549485

Abstract Magnetic resonance (MR) techniques have had a major impact in the last 10-15 years in understanding and managing multiple sclerosis. This review summarizes the current uses of MR in multiple sclerosis, based on the proceedings of a recent international workshop, under four headings: (i) technical issues; (ii) role in diagnosis; (iii) natural history studies in understanding the disease; (iv) application in clinical trials. The theory and methodology of relevant technical issues is outlined, in order to provide a framework with which to understand the potential and limitations of MR in addressing biological and clinical questions in multiple sclerosis. The principles underlying signal-to-noise and contrast-to-noise ratio are discussed, along with the techniques and clinical results for conventional and fast spin echo T2-weighted imaging, fluid-attenuated inversion recovery, detection of blood-brain barrier break down and hypointense lesions on T1-weighted images, magnetization transfer, T2 decay-curve analysis, MR spectroscopy, spinal cord imaging, diffusion imaging, and quantification of lesion load and atrophy. MRI has an extremely valuable role in confirming the clinical diagnosis of multiple sclerosis. T2-weighted brain imaging remains the standard diagnostic tool, but in some instances it is usefully complemented with gadolinium enhancement and spinal imaging. The caveat that the diagnosis of multiple sclerosis remains primarily a clinical one cannot be over-emphasized. Serial MRI studies have added much to our understanding of the natural history and pathophysiology of the disease. Blood-brain barrier breakdown is a consistent early feature of new lesion development in relapsing-remitting and secondary progressive multiple, sclerosis, and this usually correlates with active inflammation and myelin breakdown. A number of the acute MR changes are reversible, but chronic persistent abnormalities in a number of MR parameters, such as reduced N-acetyl aspartate, low magnetization transfer ratios, atrophy and T1-hypointensity, suggest the presence of demyelination and/or axonal degeneration in many chronic lesions. The presence and extent of T2-weighted MRI abnormalities at first presentation with a clinically isolated syndrome suggestive of demyelination strongly predicts the risk of developing clinically definite multiple sclerosis in the next few years. In established multiple sclerosis, however, the correlations between T2 abnormalities and disability are modest. This poor relationship partly relates to the discrepancy between lesion site and function in attempting to correlate locomotor disability with brain MRI findings. However, the correlations between brain lesion load and cognitive dysfunction in multiple sclerosis, whilst more evident, are still modest. A more important limitation is the low pathological specificity of abnormalities seen on T2-weighted images. Stronger correlations have been found between disability and new putative MR markers for demyelination and/or axonal degeneration. Serial studies using multiple MR techniques are now needed to further clarify pathophysiological mechanisms in multiple sclerosis. Serial MR has become an important tool in monitoring treatment efficacy. It provides data which can be readily analysed in a blinded fashion and which directly inspects the pathological evolution; it also enables a rapid and sensitive measure of treatment outcome in early relapsing-remitting and secondary progressive disease. Because of the modest clinical correlations it is, however, still appropriate that the definitive determinant of treatment efficacy remains a clinical one. Further work is needed to address issues of quality control in serial studies, statistical calculation of appropriate sample sizes, and optimization of the nature and frequency of MR outcomes measured. This content is only available as a PDF.

Zeki,, S;Ffytche, D, H

doi: 10.1093/brain/121.1.25pmid: 9549486

Abstract We have studied a patient, G.Y., who was rendered hemianopic following a lesion affecting the primary visual cortex (area VI), sustained 31 years ago, with the hope of characterizing his ability to discriminate visual stimuli presented in his blind field, both psychophysically and in terms of the brain activity revealed by imaging methods. Our results show that (i) there is a correlation between G.Y.'s capacity to discriminate stimuli presented in his blind field and his conscious awareness of the same stimuli and (ii) that G.Y.'s performance on some tasks is characterized by a marked variability, both in terms of his awareness for a given level of discrimination and in his discrimination for a given level of awareness. The observations on G.Y., and a comparison of his capacities with those of normal subjects, leads us to propose a simple model of the relationship between visual discrimination and awareness. This supposes that the two independent capacities are very tightly coupled in normal subjects (gnosopsia) and that the effect of a VI lesion is to uncouple them, but only slightly. This uncoupling leads to two symmetrical departures, on the one hand to gnosanopsia (awareness without discrimination) and on the other to agnosopsia (discrimination without awareness). Our functional MRI studies show that V5 is always active when moving stimuli, whether slow or fast, are presented to his blind field and that the activity in V5 co-varies with less intense activity in other cortical areas. The difference in cerebral activity between gnosopsia and agnosopsia is that, in the latter, the activity in V5 is less intense and lower statistical thresholds are required to demonstrate it. Direct comparison of the brain activity during individual 'aware' and 'unaware' trials, corrected for the confounding effects of motion, has also allowed us, for the first time, to titrate conscious awareness against brain activity and show that there is a straightforward relationship between awareness and activity, both in individual cortical areas, in this case area V5, and in the reticular activating system. The imaging evidence, together with the variability in his levels of awareness and discrimination, manifested in his capacity to discriminate consciously on some occasions and unconsciously on others, leads us to conclude that agnosopsia, gnosopsia and gnosanopsia are all manifestations of a single condition which we call the Riddoch syndrome, in deference to the British neurologist who, in 1917, first characterized the major aspect of this disability. We discuss the significance of these results in relation to historical views about the organization of the visual brain. This content is only available as a PDF.

Morris, J, S;Friston, K, J;Büchel,, C;Frith, C, D;Young, A, W;Calder, A, J;Dolan, R, J

doi: 10.1093/brain/121.1.47pmid: 9549487

Abstract Localized amygdalar lesions in humans produce deficits in the recognition of fearful facial expressions. We used functional neuroimaging to test two hypotheses: (i) that the amygdala and some of its functionally connected structures mediate specific neural responses to fearful expressions; (ii) that the early visual processing of emotional faces can be influenced by amygdalar activity. Normal subjects were scanned using PET while they performed a gender discrimination task involving static grey-scale images of faces expressing varying degrees of fear or happiness. In support of the first hypothesis, enhanced activity in the left amygdala, left pulvinar, left anterior insula and bilateral anterior cingulate gyri was observed during the processing of fearful faces. Evidence consistent with the second hypothesis was obtained by a demonstration that amygdalar responses predict expression-specific neural activity in extrastriate cortex. This content is only available as a PDF.

Samuel,, M;Caputo,, E;Brooks, D, J;Schrag,, A;Scaravilli,, T;Branston, N, M;Rothwell, J, C;Marsden, C, D;Thomas, D, G;Lees, A, J;Quinn, N, P

doi: 10.1093/brain/121.1.59pmid: 9549488

Robinson,, G;Blair,, J;Cipolotti,, L

doi: 10.1093/brain/121.1.77pmid: 9549489

Abstract In this study we report a patient (A.N.G.) who, following a malignant left frontal meningioma impinging upon Brodmann area 45, presented a 'pure' dynamic aphasia. Her spontaneous speech was markedly reduced in the absence of any syntactical impairment. Her naming, repetition and reading skills were completely normal. Two experimental investigations were carried out. The first investigation found that A.N.G. had a profound impairment in phrase and sentence generation tasks given a verbal context. However, her verbal generative skills were normal when she was asked to describe pictorial scenes and complex actions. Moreover, it was found that A.N.G. had no difficulty ordering the constituent words of a sentence. Thus, it was concluded that her verbal planning skills were intact. The second investigation tested a hypothesis that dynamic aphasia is due to an inability to select a verbal response option whenever the stimulus activates many competing verbal responses. Predictions based upon this hypothesis were confirmed on three different verbal generation tasks. It was found that our patient's grave verbal generative impairment was present for tasks involving stimuli which activate many potential responses. However, it was absent for tasks involving stimuli which activate few or only a single 'prepotent' response. The findings are discussed with reference to traditional interpretations of dynamic aphasia and more general interpretations of prefrontal cortex functioning. On the basis of a computational model of prefrontal cortex functioning, we propose that pure dynamic aphasia may be caused by damage to a 'context' module containing units responsible for selection of verbal response options. Moreover, it is suggested that our findings support the view that Brodmann area 45 is involved in verbal response generation to stimuli which activate many potential response options. This content is only available as a PDF.

Anastasopoulos,, D;Nasios,, G;Psilas,, K;Mergner,, T;Maurer,, C;Lücking, C, H

doi: 10.1093/brain/121.1.91pmid: 9549490

Abstract Vestibular and neck proprioceptive signals are known to be used in judging the locations of objects in space and relative to the body. Given that these signals are asymmetric in patients with spasmodic torticollis, one would expect such patients to have abnormal spatial perception. We tested this idea by measuring patients' perception of visual straight ahead (VSA) under various conditions: with the body in its primary position, i.e. with the head and trunk as closely aligned as possible, and after well defined passive rotations of the head and/or trunk. In the primary body position, patients' VSA direction showed considerable variations which were similar, however, to those of normal subjects; it was independent of torticollis direction, of the head torque it produced, and of the weak spontaneous nystagmus recorded in seven of the 10 patients. After whole-body rotations, i.e. where head and trunk underwent the same motion, the VSA was shifted in both patients and normal subjects, and in both groups the shift was symmetrical after rotations to the right or left. After motions where the trunk rotated under the stationary head (neck proprioceptive stimulation) or the head on the stationary trunk (combined vestibular and neck stimulus), the VSAs of normal subjects coincided rather well with their head midsagittal planes, whereas the VSAs of patients were shifted considerably towards the trunk, again in a symmetrical way. We suggest two mechanisms to explain the findings in patients: (i) a central compensation which restores symmetry of the afferent inflow in the patients (unlike the motor efference); (ii) shifting of the reference for the VSA from the head towards the trunk, because the trunk is a more reliable egocentric reference than the head in the patients. Our findings do not support the assumption that asymmetries in afferent inflow are responsible for the asymmetry of motor output in spasmodic torticollis. This content is only available as a PDF.

Fu,, L;Matthews, P, M;, De Stefano, N;Worsley, K, J;Narayanan,, S;Francis, G, S;Antel, J, P;Wolfson,, C;Arnold, D, L

doi: 10.1093/brain/121.1.103pmid: 9549491

Abstract The current study was designed to determine the relative distribution of decreases of N-acetylasparate (NAA), a marker of axonal damage, between lesions and normal-appearing white matter of patients with established multiple sclerosis and to test for associations between changes in the ratio of NAA to creatine/phosphocreatine (NAA:Cr) in those compartments and changes in disability. Data were collected from a 30-month longitudinal study of 28 patients with either a relapsing course with partial remissons and no progression between attacks (relapsing/remitting) (11 patients) or a course of progressively increasing disability, following a period of relapsing/remitting disease (secondary progressive) (17 patients). Proton magnetic resonance spectroscopic imaging (MRSI) and conventional MRI examinations were performed at 6-8-month intervals with concurrent clinical assessments of disability. General linear models were used to test associations between MRSI, MRI, lesion volume and clinical data. Analysis confirmed that the NAA:Cr ratio is lower in lesions than in the normal-appearing white matter (-15.3% in relapsing/remitting multiple sclerosis and -8.8% in secondary progressive multiple sclerosis). The lower NAA:Cr ratio per unit lesion volume previously observed for secondary progressive relative to relapsing/remitting patients was found to result from a lower ratio (8.2%, P < 0.01) in the normal-appearing white matter rather than from any differences within lesions. The importance of changes in the normal-appearing white matter was emphasized further with the observation that the NAA:Cr ratio in the normal-appearing white matter accounted for most of the observed 15.6% (P < 0.001) decrease in the NAA:Cr ratio in the brains of relapsing/remitting patients over the period of study. The decrease in the NAA:Cr ratio in normal-appearing white matter correlated strongly (P < 0.001) with changes in disability in the relapsing/remitting subgroup. These results add to data suggesting that axonal damage or loss may be responsible for functional impairments in multiple sclerosis. The accumulation of secondary axonal damage in the normal-appearing white matter may be of particular significance for understanding chronic disability in this disease. This content is only available as a PDF.

Schwarz,, M;, De Bleser, R;Poeck,, K;Weis,, J

doi: 10.1093/brain/121.1.115pmid: 9549492

Abstract Primary progressive aphasia has been clinically defined as a progressive language deficit leading to the dissolution of almost all language functions with relative preservation of other cognitive functions until late in the course of the disease. Two types of language impairment have been described for primary progressive aphasia, which differ with respect to the degree of fluency of spontaneous speech. Whereas some authors have emphasized non-fluency as a defining characteristic of primary progressive aphasia, others have proposed that phonemic rather than semantic paraphasias in naming, both in the fluent and the non-fluent subtype, should be used as a criterion to distinguish primary progressive aphasia from slowly progressive aphasia in other forms of degenerative brain disease. Patients with fluent speech and semantic dementia, as typically seen in Alzheimer's disease, produce semantic paraphasias and circumlocutions rather than phonemic errors in naming. This paper reports the long-term follow-up of a patient with fluent aphasic speech, whose language profile over a decade was similar to that of patients with semantic dementia. Neuropathological examination revealed no evidence of Alzheimer's disease. Pick's disease or Pick variant, but showed spongiform changes of cortical layers (II and III) in temporal and, less severely, in frontal gyri. The present case indicates that semantic dementia is not a reliable indicator of probable Alzheimer's disease and supports the notion that there are different subtypes of primary progressive aphasia which cannot be defined by fluency or by the presence of phonemic paraphasia. Progress in identifying the neuropathological correlates of these subtypes in cases with lobar atrophy and spongiform changes should be expected from hereditary variants of progressive disorder. This content is only available as a PDF.

Lugaresi,, E;Montagna,, P;Tinuper,, P;Plazzi,, G;Gallassi,, R;Wang, T, C;Markey, S, P;Rothstein, J, D

doi: 10.1093/brain/121.1.127pmid: 9549493

Abstract Recurring stupor can be caused by repeated metabolic, toxic or structural brain disturbances. Recently, cases of recurring stupor, with fast EEG activity were shown to display increased endogenous benzodiazepine-like activity during the episodes of stupor. Patients with recurring stupor underwent extensive metabolic and toxicologic screening, EEG and brain imaging. Endozepines and exogenously administered benzodiazepines were assayed in plasma and CSF by means of mass spectrometry. Flumazenil, a benzodiazepine antagonist was administered and the behavioural and EEG responses monitored. Treatment with oral flumazenil was attempted in selected cases. Twenty patients were found with recurring stupor. Episodes had begun between ages 18 and 67 years, and in nine patients, had disappeared spontaneously after 4-6 years with symptoms. Stupor lasted hours or days. Onset of the episodes and frequency were unpredictable. Patients were normal between attacks. Stupor was characterized by initial drowsiness, staggering and behavioural changes, followed by deep sleep and spontaneous recovery with post-ictal amnesia. Biochemical screening and brain imaging were always normal. Ictal EEG showed fast background activity, and flumazenil transiently awoke the patients and normalized the EEG. In the nine cases examined, endozepine-4 levels were increased during the stupor. Oral flumazenil reduced the frequency of the attacks in three of these nine patients. Recurring episodes of stupor may be due to increased endozepine-4. We propose the term 'endozepine stupor' for such episodes. Endozepine-4 is an endogenous ligand for the benzodiazepine recognition site at the GABAA receptor, with unknown molecular structure. This content is only available as a PDF.

Fabrigoule,, C;Rouch,, I;Taberly,, A;Letenneur,, L;Commenges,, D;Mazaux, J, M;Orgogozo, J, M;Dartigues, J, F

doi: 10.1093/brain/121.1.135pmid: 9549494

Abstract Several recent prospective studies have demonstrated the existence of a preclinical stage of dementia, identifiable by neuropsychological assessment showing impairments with a great variety of cognitive tests. However, test scores are often colinear, largely because common cognitive components are involved in different tests; in spite of an apparent heterogeneity, it is still possible that a common cognitive component may be responsible for the deterioration shown in different tests in the preclinical phase. We studied the cognitive performances of 1159 elderly residents in the PAQUID (Personnes Agées quid) cohort, at a fixed lag time of 2 years before the clinical diagnosis of dementia. Seven neuropsychological tests were administered (Mini-Mental Status Examination, Benton Visual Retention Test, Wechsler Paired-Associates Test, Isaacs Set Test, Zazzo's Cancellation Task, Digit Symbol Substitution Test and Wechsler Similarities Test). Among the initially non-demented 1159 subjects, 25 developed a dementia 2 years later, of whom 16 were classified as cases of Alzheimer's disease. In order to dissect the multicolinearity of the tests we used a multivariate approach with principal component analysis (PCA). The patients' loading on each of the first four PCA factors were subsequently correlated with the risk of dementia and Alzheimer's disease 2 years later. The logistic regression with backward stepwise selected only the first factor as an independent predictor of dementia or Alzheimer's disease. Analysis shows that there are good reasons to suspect that the first PCA factor represents a general factor corresponding to aspects of control in the tasks used. Our results therefore seem to show that preclinical deficits in dementia and Alzheimer's disease reflect the deterioration of a general cognitive factor, which may be interpreted as the disturbance of central, control processes. This content is only available as a PDF.