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... Oculomotor deficits can be found in patients who have suffered a stroke at a high percentage, ranging from 7% to 86% [18][19][20][21], depending on specific deficits, the time elapsed since the stroke, and the stage of recovery. In particular, oculomotor problems have been observed in association with specific cognitive deficits such as unilateral spatial neglect [22,23], neglect dyslexia [24,25], simultanagnosia [26], oculomotor apraxia [27], Balint syndrome [28], progressive supranuclear palsy (PSP) [29], and cerebellar ataxia [30]. ...
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The Groffman visual tracing (GVT) test is an indirect psychometric measure of oculomotor performance, used for the clinical assessment of eye movements. The test consists of two cards with five contorted lines of increasing overlap, crowding, and difficulty. The task starts from each of the letters at the top of the page, follows the line from the letter to the corresponding number at the bottom of the page, and the number is named. Although the GVT test was developed for the evaluation of children, it has also been applied to adults with visual and cognitive deficits. However, it lacks reference values. Therefore, the aim of the study was to assess oculomotor behavior across the typical human lifespan and to define normative data in an adult population. A total of 526 adults aged between 20 and 79 years, all without neurological or psychiatric deficits, were enrolled in the study. The results were analyzed by considering the accuracy and execution times separately. An influence of age, education and sex for accuracy was found, and age for the execution times was found. Norms for adults were developed considering the specific structure of the test and the accuracy and the execution time separately. The GVT test can now be applied in healthy and neurological adult populations for the evaluation of oculomotor performance.
... Clinical data favor either the "cerebellar hypothesis" or the "brainstem hypothesis" of SWJ generation. The former is based on numerous observations in neurological conditions such as Friedreich ataxia, X-linked ataxia, spinocerebellar ataxia 3, spinocerebellar ataxia 6, and oculomotor apraxia type 2. [2][3][4][5][6][7][8] Frequent SWJs have also been noted in structural cerebellar disorders such as Arnold-Chiari malformation, Langerhans cell histiocytosis, anti-GAD ataxia, and multiple sclerosis. [9][10][11][12] On the other hand, the brainstem hypothesis provides a morestraightforward explanation for the increased frequency of SWJs in PSP. ...
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Background and purpose: Square-wave jerks (SWJs) are the most common saccadic intrusion in progressive supranuclear palsy (PSP), but their genesis is uncertain. We aimed to determine the characteristics of SWJs in PSP (the Richardson subtype) and Parkinson's disease (PD) and to map the brain structures responsible for abnormal SWJ parameters in PSP. Methods: Eye movements in 12 patients with PSP, 12 patients with PD, and 12 age-matched healthy controls were recorded using an infrared corneal reflection device. The rate, mean amplitude, and velocity of SWJs were analyzed offline. Voxel-based morphometry using a 3-Tesla MRI scanner was performed to relate changes in brain volume to SWJ parameters. Results: The SWJ rate was more than threefold higher in PSP patients than in both PD patients and controls (mean rates: 33.5, 10.3, and 4.3 SWJs per minute, respectively). The volumes of neither the midbrain nor other infratentorial brain regions were correlated with the SWJ rate. Instead, highly significant associations were found for atrophy in the superior, middle, and inferior temporal gyri in the PSP group. Conclusions: SWJs in PSP are not mediated by midbrain atrophy. Instead, supratentorial cortical structures located mainly in the temporal lobe appear to be deeply involved in the generation of abnormally high SWJ rates in these patients. Known anatomical connections of the temporal lobe to the superior colliculus and the cerebellum might play a role in SWJ genesis.
... Both centrifugal and centripetal saccades should be examined as hypermetric saccades are more often found on centripetal saccades. Altered fixation and dysmetric saccades have functional consequences as daily life activities such as reading 19 or watching TV will be impaired 20 . Horizontal and vertical velocities can appear decreased in some patients though, in most of them, VO reveals severe hypometria with "multiple step saccades" resulting in a prolonged duration of total gaze shifts which can mimic slow saccades 5 ( Table 2). ...
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Whether the recessive ataxias, Ataxia with oculomotor apraxia type 1 (AOA1) and 2 (AOA2) and Ataxia telangiectasia (AT), can be distinguished by video-oculography and alpha-fetoprotein level remains unknown. We compared 40 patients with AOA1, AOA2 and AT, consecutively referred between 2008 and 2015 with 17 healthy subjects. Video-oculography revealed constant impairments in patients such as cerebellar signs, altered fixation, impaired pursuit, hypometric saccades and abnormal antisaccades. Horizontal saccade latencies could be highly increased reflecting oculomotor apraxia in one third of patients. Specific distinctive alpha-fetoprotein thresholds were determined for AOA1 (7–15 µg/L), AOA2 (15–65 µg/L) and AT (>65 µg/L). Early age onset, severe walking disability, movement disorders, sensori-motor neuropathy and cerebellar atrophy were all shared. In conclusion, alpha-fetoprotein level seems to permit a distinction while video-oculography does not and therefore is not mandatory, even if an appropriate oculomotor examination remains crucial. Our findings are that AOA1, AOA2 and AT form a particular group characterized by ataxia with complex oculomotor disturbances and elevated AFP for which the final diagnosis is relying on genetic analysis. These findings could guide genetic analysis, assist reverse-phenotyping and provide background for the interpretation of the numerous variants of unknown significance provided by next-generation sequencing.
... 9,24 There is growing evidence that cerebellar abnormalities that are not necessarily indicated by lesions can contribute to disability, including cognitive impairment in MS. 6 In context with neuropsychological testing of patients with MS, one should keep in mind that cerebellar impairment could also bias neuropsychological performance by, for example, altering oculomotor functions and thus reading abilities. 25 However, considering that the cerebellum is highly involved in executive functions including working memory, visuo-spatial functions, language, procedural learning, and attention 26,27 due to is involvement in functional loops with the frontal, superior temporal, limbic, and posterior parietal cortex in MS, our findings may be of relevance for a better understanding of executive deficits in patients with RRMS. ...
Article
Evidence for early, non-lesional cerebellar damage in patients with multiple sclerosis: DTI measures correlate with disability, atrophy, and disease duration Abstract Background: Common symptoms of multiple sclerosis (MS) such as gait ataxia, poor coordination of the hands, and intention tremor are usually the result of dysfunctionality in the cerebellum. Magnetic resonance imaging (MRI) has frequently failed to detect cerebellar damage in the form of inflammatory lesions in patients presenting with symptoms of cerebellar dysfunction. Objective: To detect microstructural cerebellar tissue alterations in early MS patients with a “normal appearing” cerebellum using diffusion tensor imaging (DTI). Methods: 68 patients with relapsing-remitting MS and without cerebellar lesions and 26 age-matched healthy controls were admitted to high-resolution MRI and DTI to assess microstructure and volume of the cerebellar white matter (CBWM). Results: We found cerebellar fractional anisotropy (FA) and CBWM volume reductions in the group of 68 patients. Interestingly, a subgroup of these patients that was derived by including only patients with early and mild MS (N=23, median age 30 y, median EDSS=1.5, median duration 28 months) showed already cerebellar FA but no CBWM volume reductions. FA reductions were correlated with disability, atrophy, and disease duration. Conclusion: “Normal appearing” cerebellar WM can be damaged in a very early stage of RRMS. DTI seems to be a sensitive tool for detecting this hidden cerebellar damage.
... Increased latencies and reduced range of saccades are the hallmark of oculomotor apraxia. 13 Clinically, oculomotor apraxia was established in case 2, but only variably present in case 1. On oculography, cases 1 and 2 generated only few saccades or sac- cades with low amplitudes. ...
Chapter
Ocular motor apraxia is a syndrome of gaze shifting failure, mainly saccades, in which patients show absent or highly delayed voluntary eye movements, although other eye movements can be preserved. One phenotype is characterized by absent or great disability to perform horizontal and vertical voluntary gaze shifting, with preservation of slow and quick phases of vestibular nystagmus. It is observed in acute brain lesions and adult-onset neurodegenerative diseases and results from dysfunction of cortical (and basal ganglia) control of voluntary eye movements. The congenital form, renamed “infantile-onset saccade initiation delay,” is characterized by head thrust, highly hypometric staircase saccades, increased saccade latency, and impaired quick phases of nystagmus. It may result from involvement of superior collicular, cerebellar, and/or cerebrocerebellar circuits of conjugate gaze shifting. This last phenotype is close to the one associated with Joubert syndrome, some Gaucher disease patients, ataxia-telangiectasia, and ataxia with oculomotor apraxia.
Article
Objective: To identify the pathogenic gene for a Chinese Han consanguineous marriage family with autosomal recessive cerebellar ataxia by homozygosity mapping and mutation analysis. Methods: Six members of the family were enrolled in this study, including 3 patients, the unaffected sibling and their parents of first cousin marriage. After excluding GAA repeats mutation of FXN gene, whole-genome single nucleotide polymorphism (SNP) microarray scanning and homozygosity mapping were performed to localize the candidate gene. The coding regions and intronic flanking sequences of the candidate genes were analyzed. Results: Four candidate regions were identified, including 2p25.3, 9q22.2-34.3, 13q12.3-14.3 and 17p13. The SETX gene localizing in 9q22.2-34.3 that is responsible for ataxia with oculomotor apraxia 2 was analyzed at first. There were 4 mutations in exon 10, including three missense mutations (c.3576T>G, p. D1192E; c. 3754G>A, p. G1252R; c. 4156A>G, p. I1386V) and a deletion mutation (c.5084_5087delAGTC, p. Q1695_S1696del). Three patients were homozygous of the 4 mutations, an unaffected sibling was normal, and their parents were heterozygous of 4 mutations. Conclusions: The pathogenic haplotype comprising four mutations of the SETX gene was identified in the consanguinity family. c. 5084_5087delAGTC (p.Q1695_S1696del) is a novel mutation. The affected individuals of this family were characterized by mild phenotype and slow progress without oculomotor apraxia, indicating the clinical variability of the disease.
Article
Cerebellar ataxia is an uncommon manifestation of hypothyroidism with unknown pathomechanism. The few descriptions of the clinical phenotype range from limb, gait, and trunk ataxia to various ocular motor abnormalities. We evaluated a 62-year-old woman with previously undetected severe hypothyroidism who presented with prominent saccadic intrusions and gait ataxia. She had high titers of antithyroid autoantibodies and anti-glutamic acid decarboxylase (anti-GAD) antibodies. Horizontal eye movement recordings revealed a series of nearly continuous pseudoharmonic square wave jerks (SWJs) constituting a square wave oscillation. Amplitudes reached maximum values of about 4, and wave frequency approached 100 cycles per minute. Thyroxine substitution and corticosteroid administration had little effect on SWJ parameters. The square wave oscillation nearly completely resolved after a single treatment session with intravenous immunoglobulin suggesting a causal link between an autoimmune process and the cerebellar dysfunction. Current concepts of the genesis of saccadic intrusions favor a role for anti-GAD antibodies in the etiology of SWJs.
Article
The cerebellum is responsible for refining ocular movements, thereby guaranteeing the best possible visual acuity and clarity despite changes in body or head positions or movement of the object of interest. The cerebellum is involved in the control of all eye movements, in their real-time, immediate modulation, and in their long-term adaptive calibration. The flocculus-paraflocculus complex and the caudal vermis (nodulus and uvula) together constitute the vestibulocerebellum. Lesions affecting these different regions give rise to 3 principal clinical cerebellar syndromes. This article discusses the various neuro-ophthalmic manifestations of various cerebellar disorders, as well as some therapeutic options for oscillopsia. Copyright © 2014 Elsevier Inc. All rights reserved.
Article
This work reviews saccadic intrusions focusing on recent developments in pathophysiology and treatment. Saccadic intrusions have been recognized as features of oculomotor apraxia type 2 and neuromyelitis optica. Novel fixation instabilities have been identified such as 'staircase' square wave jerks, or the pervasive ocular microtremor seen in Parkinson's disease. Although evidence supports a network underlying the pathophysiology of square wave jerks involving cerebral hemispheres, subcortex, brainstem and cerebellum, the debate regarding the pathogenesis of ocular flutter and opsoclonus centres on a cerebellar and brainstem hypotheses. The cerebellar hypothesis explains functional imaging findings, whereas the brainstem hypothesis provides possible explanations for some therapeutic responses as well as accompanying myoclonus, startle and tremor. A study of immunotherapies in children with opsoclonus-myoclonus syndrome found that treatment combinations were more effective than corticotropin alone. Recognition of saccadic intrusions can assist in the diagnosis of neurological disease. We are gaining new insights about pathogenesis through models, functional imaging and genetic approaches.
Article
Saccadic eye movements are traditionally cited as an especially successful combination of accuracy and velocity, such high level of performances being believed to be crucial for optimal vision. Although the structures subtending these properties are now well recognized, very little is known about the functional consequences on visually guided behaviors of reduced saccade performances, i.e., slowness and/or inaccuracy. We therefore investigated the impact of such impairments in patients with spino-cerebellar and Friedreich ataxia, i.e., diseases known to affect both saccade parameters. Subjects performed a classical eye movement task, in order to quantify saccade inaccuracy and/or slowness, a visually search task and a reading task and completed a questionnaire designed to evaluate their perceived visual discomfort in daily activities. The first main result was that saccade impairments did have an impact on visually guided behaviors, resulting in an increased time for target detection, especially when accurate foveation was needed, and in an increased reading time. The main responsible oculomotor factor was increased variability of saccade accuracy, and the least responsible factor was reduced saccade velocity. The second main result was that saccade disorders did not induce significant subjective discomfort, since no correlations were found between the results of the questionnaire and saccade parameters. These results emphasize the functional impact of increased variable error of saccade accuracy and question the rationale of high saccade velocities. The discrepancy between objective and subjective measures underlines the largely unconscious aspect of saccade control and leads us to consider the need for an adapted therapy.
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This study aimed at investigating the clinical usefulness of the Mental Deterioration Battery (MDB) in the neuropsychological diagnosis and characterization of the dementia syndrome. In this paper, we report: (a) normative data for various test scores derived from the analysis of performance of 340 normal subjects living in urban areas; (b) an evaluation of the reliability of the single tests and of the battery as a whole in differentiating normal subjects from patients affected by cognitive deterioration derived from the analysis of performance of 130 normal subjects living in rural areas and 134 patients affected by probable Alzheimer’s dementia; (c) a cluster analysis of performances of the 340 normal subjects in the standardization group to evaluate possible criteria of homogeneity according to which the various MDB scores tend to aggregate; (d) an analysis of performance profiles of 183 patients with right monohemispheric focal lesions, 159 patients with left unilateral lesions with aphasia and 131 left-lesioned nonaphasic patients to evaluate the specificity of the single tests of the battery in documenting a selective impairment of one of the two cerebral hemispheres. Results confirm the reliability of the MBD in discriminating between normal and demented patients and provide indications for use of the battery in differentiating qualitative patterns of cognitive impairment.
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Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.
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The frequency of square wave jerks (SWJ) was compared in eight patients with progressive supranuclear palsy (PSP), 25 patients with multiple system atrophy or Parkinson's disease plus (MSA/PP), 85 patients with idiopathic Parkinson's disease (PD) and 20 age-matched normal volunteers. In the control group, the mean (SD) SWJ frequency (SWJ larger than 1 degree amplitude) was 2.3 (2.4)/min. Abnormal ocular fixation (SWJ frequency greater than 10/min) was observed in a large proportion of PSP patients (7/8) and of MSA/PP patients (16/25) but in few PD patients (13/85). In the group of PD patients with abnormal ocular fixation, freezing of gait, falls and instability were more severe than in the group of PD patients with normal fixation. The study of ocular fixation may help to differentiate PD clinically from other Parkinsonian syndromes. SWJ are probably not related to the central degeneration of the dopaminergic nigrostriatal pathway observed in PD.
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An information-processing model is outlined that predicts that performance on non-routine tasks can be impaired independently of performance on routine tasks. The model is related to views on frontal lobe functions, particularly those of Luria. Two methods of obtaining more rigorous tests of the model are discussed. One makes use of ideas from artificial intelligence to derive a task heavily loaded on planning abilities. A group of patients with left anterior lesions has a specific deficit on the task. Subsidiary investigations support the inference that this is a planning impairment.
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This study aimed at investigating the clinical usefulness of the Mental Deterioration Battery (MDB) in the neuropsychological diagnosis and characterization of the dementia syndrome. In this paper, we report: (a) normative data for various test scores derived from the analysis of performance of 340 normal subjects living in urban areas; (b) an evaluation of the reliability of the single tests and of the battery as a whole in differentiating normal subjects from patients affected by cognitive deterioration derived from the analysis of performance of 130 normal subjects living in rural areas and 134 patients affected by probable Alzheimer's dementia; (c) a cluster analysis of performances of the 340 normal subjects in the standardization group to evaluate possible criteria of homogeneity according to which the various MDB scores tend to aggregate; (d) an analysis of performance profiles of 183 patients with right monohemispheric focal lesions, 159 patients with left unilateral lesions with aphasia and 131 left-lesioned nonaphasic patients to evaluate the specificity of the single tests of the battery in documenting a selective impairment of one of the two cerebral hemispheres. Results confirm the reliability of the MBD in discriminating between normal and demented patients and provide indications for use of the battery in differentiating qualitative patterns of cognitive impairment.
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Two cancellation/attentional tasks: (i) Lines Cancellation (LC) and Multiple Features Targets Cancellation (MFTC) and (ii) a standard battery of neuropsychological tests, the Mental Deterioration Battery (MDB), were administered to 68 patients with dementia of the Alzheimer's type (DAT) and 40 patients with multi-infarct dementia (MID), who were accurately matched for the overall severity of dementia, and to 40 normal controls. Both accuracy and time of execution were considered in evaluating performance on the two cancellation tasks, which involved visuospatial exploration and psychomotor speed, but were differently demanding in terms of selective attention. On the first cancellation task (LC), requiring a lower attentional load, the two demented patient groups performed at the same level of accuracy. On the second cancellation task (MFTC), which was more demanding in terms of selective and divided attention, DAT patients were significantly less accurate than MID patients, making a higher number of 'false-alarm' errors. Conversely, the time employed in the execution of both LC and MFTC took longer for MID than for DAT patients, suggesting a greater impairment of psychomotor speed in MID. In the MDB, DAT patients scored significantly worse than MID patients on several measures of episodic memory (the immediate recall, delayed recall and delayed recognition of Rey's Auditory Verbal Learning Test) and on a test of visual-spatial memory. These data suggest that, while psychomotor speed and the lower (sensorimotor) levels of attention are preferentially impaired in subcortical forms of dementia such as MID, the higher levels of selective and divided attention are more markedly disrupted in the Alzheimer type of dementia.
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Ataxia with oculomotor apraxia type 2 (AOA2) is a newly described autosomal recessive cerebellar ataxia (ARCA) defined by genetic location to 9q34 of three families sharing gait ataxia, oculomotor apraxia and/or elevated alpha-foetoprotein (AFP) levels. We have evaluated 77 families with progressive non-Friedreich ARCA and have identified six families with a phenotype suggestive of AOA2. Linkage was confirmed in all six families, with a maximal lod score of 5.91 at D9S1830. We report the first detailed phenotypic study, including neuropsychological, oculographic and brain imaging investigations, in the largest series of AOA2 patients yet recruited. The mean age at onset was 15.1 +/- 3.8 years. Sensory motor neuropathy (92%) and choreic or dystonic movements (44%) were frequent. Oculomotor apraxia was observed in 56% of patients and characterized by increased horizontal saccade latencies and hypometria. AFP levels were elevated in 100% of the families, making it a useful biological marker. This study shows for the first time that AOA2 can be found in Europe, North Africa and the West Indies, and its relative frequency represents approximately 8% of non-Friedreich ARCA, which is more frequent than ataxia telangiectasia and ataxia with oculomotor apraxia type 1 (AOA1), in our series of adult patients. In adults, AOA2 may be, therefore, the most frequent cause of ARCA identified so far, after Friedreich's ataxia.
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Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination.
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Primary fixation is never perfectly stable, but is frequently interrupted by slow drifts, microsaccades and saccadic intrusions (SI). SI are involuntary, conjugate movements which take the form of an initial fast movement away from the desired eye position and followed after a short duration, by either a return secondary saccade or a drift. The purpose of this study was to examine the prevalence and metrics of SI in a population of 50 healthy subjects. Using both one and two dimensional recordings we find that all 50 members of the subject group exhibited SI. The SI were bilateral, conjugate and horizontal. No purely vertical SI were detected when examined in three subjects. SI amplitude mean and range was 0.6 degrees +/-0.5 degrees, 0.1 degrees -4.1 degrees; SI frequency mean and range was 18.0+/-14.3 per min, 1.0-54.8 per min; SI duration mean and range was 225+/-150, 20-870 ms. The mean SI amplitude and frequency when SI<0.5 degrees were removed was 0.97 degrees +/-0.56 degrees and 7.0+/-11.4 per min respectively. Age was positively correlated with SI amplitude (p<0.01), but there was no correlation between age and SI frequency. Three of four types of SI monophasic square wave intrusions (MSWI), biphasic square wave intrusions (BSWI) and double saccadic pulses (DSP) were found to be exclusively saccadic, whilst the fourth type, the single saccadic pulses (SSP), were confirmed to exhibit a slow secondary component. MSWI were the most frequently observed SI occurring in 47 out of 50 (94%) of the subjects with a mean amplitude, frequency and duration of 0.7 degrees +/-0.5 degrees, 11.5+/-11.6 per min, and 255+/-147 ms respectively. Mean amplitudes and frequencies for BSWI (n=20), SSP (n=11) and DSP (n=34) were found to be 0.50 degrees +/-0.2 degrees, 1.2+/-2.5 per min; 0.40 degrees +/-0.20 degrees, 0.4+/-1.0 per min and 0.3 degrees +/-0.4 degrees, 5.0+/-8.7 per min respectively. No differences in MSWI characteristics were found between binocular and monocular viewing. Possible explanations for SI occurrence include experimental viewing conditions, subject fatigue and covert shifts in attention.
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Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age 10 and 22 years, cerebellar atrophy, peripheral neuropathy, oculomotor apraxia (OMA), and elevated serum alpha-fetoprotein (AFP) levels. Recessive mutations in SETX have been described in AOA2 patients. To describe the clinical features of AOA2 and to identify the SETX mutations in 10 patients from four Italian families. The patients underwent clinical examination, routine laboratory tests, nerve conduction studies, sural nerve biopsy, and brain MRI. All were screened for SETX mutations. All the patients had cerebellar features, including limb and truncal ataxia, and slurred speech. OMA was observed in two patients, extrapyramidal symptoms in two, and mental impairment in three. High serum AFP levels, motor and sensory axonal neuropathy, and marked cerebellar atrophy on MRI were detected in all the patients who underwent these examinations. Sural nerve biopsy revealed a severe depletion of large myelinated fibers in one patient, and both large and small myelinated fibers in another. Postmortem findings are also reported in one of the patients. Four different homozygous SETX mutations were found (a large-scale deletion, a missense change, a single-base deletion, and a splice-site mutation). The clinical phenotype of oculomotor apraxia type 2 is fairly homogeneous, showing only subtle intrafamilial variability. OMA is an inconstant finding. The identification of new mutations expands the array of SETX variants, and the finding of a missense change outside the helicase domain suggests the existence of at least one more functional region in the N-terminus of senataxin.
Article
Two cancellation/attentional tasks: (i) Lines Cancellation (LC) and Multiple Features Targets Cancellation (MFTC) and (ii) a standard battery of neuropsychological tests, the Mental Deterioration Battery (MDB), were administered to 68 patients with dementia of the Alzheimer's type (DAT) and 40 patients with multi-infarct dementia (MID), who were accurately matched for the overall severity of dementia, and to 40 normal controls. Both accuracy and time of execution were considered in evaluating performance on the two cancellation tasks, which involved visuospatial exploration and psychomotor speed, but were differently demanding in terms of selective attention. On the first cancellation task (LC), requiring a lower attentional load, the two demented patient groups performed at the same level of accuracy. On the second cancellation task (MFTC), which was more demanding in terms of selective and divided attention, DAT patients were significantly less accurate than MID patients, making a higher number of `false-alarm' errors. Conversely, the time employed in the execution of both LC and MFTC took longer for MID than for DAT patients, suggesting a greater impairment of psychomotor speed in MID. In the MDB, DAT patients scored significantly worse than MID patients on several measures of episodic memory (the immediate recall, delayed recall and delayed recognition of Rey's Auditory Verbal Learning Test) and on a test of visual–spatial memory. These data suggest that, while psychomotor speed and the lower (sensorimotor) levels of attention are preferentially impaired in subcortical forms of dementia such as MID, the higher levels of selective and divided attention are more markedly disrupted in the Alzheimer type of dementia.
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Despite the involvement of cerebellar ataxia in a large variety of conditions and its frequent association with other neurological symptoms, the quantification of the specific core of the cerebellar syndrome is possible and useful in Neurology. Recent studies have shown that cerebellar ataxia might be sensitive to various types of pharmacological agents, but the scales used for assessment were all different. With the long-term goal of double-blind controlled trials —multicentric and international — an ad hoc Committee of the World Federation of Neurology has worked to propose a one-hundred-point semi-quantitative International Cooperative Ataxia Rating Scale (ICARS). The scale proposed involves a compartimentalized quantification of postural and stance disorders, limb ataxia, dysarthria and oculomotor disorders, in order that a subscore concerning these symptoms may be separately studied. The weight of each symptomatologic compartment has been carefully designed. The members of the Committee agreed upon precise definitions of the tests, to minimize interobserver variations. The validation of this scale is in progress. © 1997 Elsevier Science B.V. All rights reserved.
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A group of sixty-six adult subjects was given the task of producing as many words as possible beginning with specified letters of the alphabet. The number of words produced during a period of 60 sec correlated highly both with a frequency count derived from the Thorndike-Lorge norms and with estimates derived from the dictionary of the number of words in the English language beginning with each letter. In a second experiment, eight letters representing three levels of difficulty as found in normal subjects were given to thirty brain-damaged and thirty hospitalized control patients. Results in terms of verbal productivity indicated that, for patients of high intelligence, difficult letters (i.e. J and U) showed the greatest discrimination. On the other hand, for patients of low intelligence, easy letters (i.e. F, S, P and T) were more effective in differentiating the brain-damage and control groups. The findings also indicated that difficult letters may be particularly effective in distinguishing between patients with right and left hemisphere damage. An analysis of order of presentation indicated that practice and fatigue effects were not related to verbal fluency when as many as eight letters were administered. It is suggested that the addition of difficult letters to standard word fluency tests may yield more precise discriminations between brain-damaged and control patients when overall level of intellectual functioning is taken into account.
Article
Clinical, experimental and neuroimaging studies indicate that the cerebellum is involved in neural processes beyond the motor domain. Cerebellar somatotopy has been shown for motor control, but topographic organization of higher-order functions has not yet been established. To determine whether existing literature supports the hypothesis of functional topography in the human cerebellum, we conducted an activation likelihood estimate (ALE) meta-analysis of neuroimaging studies reporting cerebellar activation in selected task categories: motor (n = 7 studies), somatosensory (n = 2), language (n = 11), verbal working memory (n = 8), spatial (n = 8), executive function (n = 8) and emotional processing (n = 9). In agreement with previous investigations, sensorimotor tasks activated anterior lobe (lobule V) and adjacent lobule VI, with additional foci in lobule VIII. Motor activation was in VIIIA/B; somatosensory activation was confined to VIIIB. The posterior lobe was involved in higher-level tasks. ALE peaks were identified in lobule VI and Crus I for language and verbal working memory; lobule VI for spatial tasks; lobules VI, Crus I and VIIB for executive functions; and lobules VI, Crus I and medial VII for emotional processing. Language was heavily right-lateralized and spatial peaks left-lateralized, reflecting crossed cerebro-cerebellar projections. Language and executive tasks activated regions of Crus I and lobule VII proposed to be involved in prefrontal-cerebellar loops. Emotional processing involved vermal lobule VII, implicated in cerebellar-limbic circuitry. These data provide support for an anterior sensorimotor vs. posterior cognitive/emotional dichotomy in the human cerebellum. Prospective studies of multiple domains within single individuals are necessary to better elucidate neurobehavioral structure–function correlations in the cerebellar posterior lobe.
Chapter
Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age three and 30 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia, and elevated serum concentration of alpha-fetoprotein (AFP). The diagnosis of AOA2 is based on clinical and biochemical findings, family history, and exclusion of the diagnosis of ataxia-telangiectasia and AOA1. AOA2 is associated with mutations in SETX, the gene that encodes the protein senataxin. Molecular genetic testing is available on a clinical basis. Treatment of manifestations: Physical therapy for disabilities resulting from peripheral neuropathy; wheelchair for mobility as needed; educational support (e.g., computer with speech recognition and special keyboard for typing) to compensate for difficulties in reading (caused by oculomotor apraxia) and in writing (caused by upper-limb ataxia). Surveillance: Routine follow-up with a neurologist. AOA2 is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family have been identified.
Article
The Bells Test, a cancellation task, permits a quantitative and qualitative evaluation of visual neglect. The construction of the test allows for rapid visualization of the spatial distribution of the omitted targets and their quantification. The examiner can also obtain a qualitative picture through an approximation of the visual scanning pattern used by the subject; this provides valuable information on 'how' the task is performed. In summary, the Bells Test is a more dynamic, and thus, more sensitive clinical examination for visual neglect.
Article
In this paper we review the basic anatomy and functional localization in the cerebellum. Experimental anatomical studies emphasize the predominance of skeletomotor and visuomotor connections. Parietal lobe visual inputs arise principally from the dorsal stream extrastriate visual areas, which are specialized for the visual control of movement. There are few or no inputs to the cerebellum from inferotemporal cortex. Much of the input from prefrontal cortex is from areas that control eye movements. Comparative anatomical studies of the hominoid dentate nucleus are consistent with the role of much of the cerebellar hemispheres in the visual guidance of movement. Although some mossy and climbing fibre afferents to the cerebellum are reciprocally organized, feeding back onto their original source, the reciprocity does not exist for the visuomotor division. The dorsal paraflocculus receives its mossy fibres from extrastriate areas of the dorsal visual stream, and projects to the frontal eye fields. Functional magnetic resonance imaging (fMRI) studies in human subjects confirm the presence of somatotopically organized anterior and posterior skeletomotor areas with eye movement activity centred in the oculomotor vermis. Oculomotor and skeletomotor representation extend into adjacent Crus I and II. Discrepancies between the results of imaging studies in human subjects and experimental data are discussed. Skeletomotor activity or eye movements may contaminate many fMRI studies of putative cognitive functions of the cerebellum.
Article
Anatomical, experimental, functional neuroimaging, and clinical data implicate the importance of corticocerebellar interactions in many nonmotor domains, such as sensory, cognitive, emotional, and affective processing. The modular organization and multifarious domains of activity suggest that cerebellar functional specificity has to be searched in a processing modality that is applicable to various contexts. One theory, among many, proposes that "sequence in" of sensory information is critical to understand cerebellar functioning. Here, we aimed at reinterpreting previous findings according to the cerebellar "sequence detection" theory. Spatial function, language, verbal memory, and sequence processing all are domains that are reported impaired after cerebellar damage. Reviewing data that have focused on sequential information processing highlighted the importance of the cerebellum in detecting patterns of incoming stimuli or in central circuit activities. Cerebellar sequence processing should be considered within the known organization of cerebellocortical connections. Within this framework, depending on the involved loop, cerebellar damage can provoke different functional impairments such as defective processing of sensorial stimuli sequences; defective sequential detection error-based learning; defective comparison between incoming sensory patterns and internal modules, and so on.
Article
Ataxia with oculo-motor apraxia type 2 (AOA2) is a recently described autosomal recessive cerebellar ataxia (ARCA) caused by mutations in the senataxin gene (SETX). We analysed the phenotypic spectrum of 19 AOA2 patients with mutations in SETX, which seems to be the third most frequent form of ARCA in Algeria after Freidreich ataxia and Ataxia with vitamin E deficiency. In AOA2 patients, the mean age at onset for all families was in the second decade. Cerebellar ataxia was progressive, slowly leading to disability which was aggravated by axonal polyneuropathy present in almost all the patients. Mean disease duration until wheelchair was around 20 years. Oculo-motor apraxia (OMA) was present in 32% of the patients while convergent strabismus was present in 37%. Strabismus is therefore also very suggestive of AOA2 when associated with ataxia and polyneuropathy even in the absence of OMA. Cerebellar atrophy was more severe in the eldest patients; however it may also be an early sign since it was present in the youngest and paucisymptomatic patients. The initial sign was gait ataxia in all but two patients who presented with head tremor and writer cramp, respectively. Serum alpha-fetoprotein, which was elevated in all tested patients, was a good marker to suggest molecular studies of the SETX gene.
Article
One hundred and twenty nine patients affected by a cerebral lesion confined to a single lobe, underwent a battery of tests including the "Temporal Rule Induction" (TRI) and the Raven's "Coloured Progressive Matrices" (CPM). Frontal patients scored lower than any other group on TRI and parietal patients on CPM. This contrasting pattern of performance provides strong empirical support to the hypothesis that the frontal lobe is specifically involved in tasks that require a control on temporally ordered information whereas the parietal lobe is concerned with cognitive activities that imply visuo-spatial analysis.
Article
Despite the involvement of cerebellar ataxia in a large variety of conditions and its frequent association with other neurological symptoms, the quantification of the specific core of the cerebellar syndrome is possible and useful in Neurology. Recent studies have shown that cerebellar ataxia might be sensitive to various types of pharmacological agents, but the scales used for assessment were all different. With the long-term goal of double-blind controlled trials-multicentric and international-an ad hoc Committee of the World Federation of Neurology has worked to propose a one-hundred-point semi-quantitative International Cooperative Ataxia Rating Scale (ICARS). The scale proposed involves a compartimentalized quantification of postural and stance disorders, limb ataxia, dysarthria and oculomotor disorders, in order that a subscore concerning these symptoms may be separately studied. The weight of each symptomatologic compartment has been carefully designed. The members of the Committee agreed upon precise definitions of the tests, to minimize interobserver variations. The validation of this scale is in progress.
Article
Ten subjects who could be reliably assessed as surface dyslexics were selected on the basis of a large test battery. Eye movements in non-linguistic and linguistic tasks were studied in these subjects. Stability of fixation on a stationary stimulus was examined. Performance of dyslexics was no different from that of an age-matched control group. Similarly, no difference was observed between the two groups when they were requested to saccade to a rightward or leftward target. On the other hand, while reading short passages, dyslexics showed an altered pattern of eye movements with more frequent and smaller rightward saccades as well as longer fixation times. The reading pattern was analysed by eye tracking. Numerous fixations were used to read a single word in a fragmented way. Longer words showed a higher number of fixations. Overall, it was concluded that surface dyslexia is not associated with oculo-motor dysfunction and the study of eye movements in reading reveals the processing through orthography-to-phonology conversion characteristic of surface dyslexia. The importance is stressed of examining selected groups of subjects in the psychophysiological study of dyslexia.
Article
For many researchers, eye-movement measures have become instrumental in revealing the moment-to-moment activity of the mind during reading. In general, there has been a great deal of consistency across studies within the eye-movement literature, and researchers have discovered and examined many variables involved in the reading process that affect the nature of readers' eye movements. Despite remarkable progress, however, there are still a number of issues to be resolved. In this article, we discuss three controversial issues: (1) the extent to which eye-movement behavior is affected by low-level oculomotor factors versus higher-level cognitive processes; (2) how much information is extracted from the right of fixation; and (3) whether readers process information from more than one word at a time.
Article
The newly recognized ataxia-ocular apraxia 1 (AOA1; MIM 208920) is the most frequent cause of autosomal recessive ataxia in Japan and is second only to Friedreich ataxia in Portugal. It shares several neurological features with ataxia-telangiectasia, including early onset ataxia, oculomotor apraxia and cerebellar atrophy, but does not share its extraneurological features (immune deficiency, chromosomal instability and hypersensitivity to X-rays). AOA1 is also characterized by axonal motor neuropathy and the later decrease of serum albumin levels and elevation of total cholesterol. We have identified the gene causing AOA1 and the major Portuguese and Japanese mutations. This gene encodes a new, ubiquitously expressed protein that we named aprataxin. This protein is composed of three domains that share distant homology with the amino-terminal domain of polynucleotide kinase 3'- phosphatase (PNKP), with histidine-triad (HIT) proteins and with DNA-binding C2H2 zinc-finger proteins, respectively. PNKP is involved in DNA single-strand break repair (SSBR) following exposure to ionizing radiation and reactive oxygen species. Fragile-HIT proteins (FHIT) cleave diadenosine tetraphosphate, which is potentially produced during activation of the SSBR complex. The results suggest that aprataxin is a nuclear protein with a role in DNA repair reminiscent of the function of the protein defective in ataxia-telangiectasia, but that would cause a phenotype restricted to neurological signs when mutant.
Article
The pattern of eye movements during reading was studied in 12 developmental dyslexics and in 10 age-matched controls. According to standard reading batteries, dyslexics showed marked reading slowness and prevalently used the sublexical procedure in reading. Eye movements were recorded while they read lists of short and long words or pseudowords. In normal readers, saccade amplitude increased with word length without a concomitant change in the number of saccades; in contrast, the number of saccades increased for long pseudowords. In dyslexics, the eye movement pattern was different. The number of saccades depended on stimulus length for both words and pseudowords while saccade amplitude remained small and constant. The sequential scanning shown by dyslexics for both words and pseudowords appears consistent with the cognitive description of the reading disorder which indicates the preferential use of the sublexical print-to-sound correspondence rules.
Article
The effect of crowding on the identification of words was examined in normal readers and subjects with developmental dyslexia. In Experiment 1, a matching task was used. Words were presented either alone or embedded in other words. Vocal reaction times (RT) of dyslexics were slower and more sensitive to the presence of the surrounding stimuli than those of control subjects. Similar results were obtained in a control experiment using the same task for strings of symbols (isolated or crowded) instead of words. These data indicate that differences in crowding in control and dyslexic subjects arise at a pre-linguistic level. In Experiment 2, vocal RTs to word reading were measured. Two conditions putatively reducing the effect of crowding were tested: increasing inter-letter spacing and blurring. A moderate increase of inter-letter spacing produced faster vocal RTs in dyslexics, while no effect was present in normal controls. Moderate blurring of stimuli did not change dyslexics' RTs, while normal readers became slower. Group and individual results are discussed to evaluate the extent to which crowding contributes to the genesis of developmental dyslexia.
Article
This study examined the influence of rapid automatization naming (RAN) measures on various parameters of reading performance in children who were native speakers of a language with a shallow orthography (Italian). Participants included 281 children enrolled in first-to-sixth grade. They were given a Naming test, in which they had to name rapidly matrices of colors, objects, or digits, a Cancellation test, using the same stimulus materials, and an oral Articulation test. Performance on all tests improved steadily across ages tested. Performance on the Naming test, but not on the Cancellation and Articulation tests, predicted speed and accuracy in reading; none of these measures reliably predicted the reading comprehension measure. Data on a Blending test were also available for a subsample of first- and third-graders. Both RAN and phonological ability contributed independently to the prediction of reading ability (accuracy and speed) in these participants. The results extend observations on RAN to an orthographically shallow language (Italian) and suggest an element of continuity between languages with opaque and transparent orthographies.
Article
A non-predictive peripheral cueing paradigm was used to evaluate visuospatial attentional deficits in symptomatic HD patients, employing spatially valid and invalid visual cues over a range of stimulus onset asynchronies (SOA) to elicit a saccadic response. Although both patients and controls demonstrated initial facilitation for valid versus invalid cues following the shortest SOA, and a performance decrement (inhibition of return), at the longest SOA, a clear differentiation between these groups was found for the intermediate SOAs. Unlike controls, where IOR manifested between 350 and 1000 ms, IOR was evident as early as 150 ms for HD patients. Further, the benefit of valid cueing correlated significantly with the level of impairment. Although patients exhibited poor fixation, principally attributable to saccadic intrusions, they were capable of appropriately suppressing a purely stimulus-driven response to the cue. A similar proportion of erroneous saccades to the cue were generated by both groups prior to stimulus onset, also correlating significantly with level of impairment. These results are discussed with respect to neural processes implicated in spatial cueing and within the context of reduced inhibitory activity of the BG in HD.
Article
A 36-item-version of the Token Test is described and normative data obtained from its administration to 215 normal subjects are given. Years of schooling (but not age) were found to significantly affect the performance. The scores were corrected for this factor and the lower limit of the 90% tolerance interval around the mean of the adjusted scores was determined: it was found to correspond to 29 and left below it exactly 5% of the normal sample. The test was given to 200 aphasic patients. Fourteen (7%) were found to have an adjusted score of 29 or more, namely would have been classified as non-aphasic. This is a percentage remarkably smaller than that (40%) obtained with a 10 sentence comprehension test, which supports previous studies pointing to the sensitivity of the Token Test to the presence of oral language disorders. On the basis of the aphasic patients' performance, cutting scores allowing evaluation of the severity of the comprehension deficit are provided. The 36-item-version of the test appears to be an useful and convenient device to diagnose aphasic impairment of language comprehension.
Article
The aim of the present study was to verify the hypothesis advanced by Hécaen and Assal (1970), that the presence of landmarks can improve the copying performance of left brain-damaged patients, while leaving unchanged that of right brain-damaged patients. Sixty-two control subjects and 196 brain-damaged patients with lesions restricted to the right (N = 84) or to the left (N = 112) cerebral hemisphere were given two tests of copying drawings. In the first task the patients were asked to directly copy a drawing; to perform the second test they were given guiding landmarks. On both tests no difference was found between the performance of the two hemispheric groups. Right-sided patients used a lower number of guiding landmarks, but this occurred only on the half of the drawings contralateral to the side of the lesion and was apparently due to unilateral spatial neglect.
Article
The effect of lexicality and stimulus length was studied in 32 third- and fourth-grade Italian dyslexics and in 86 age-matched controls. A visual lexical decision task was used. As proposed by Faust et al. (1999)4. Faust , M. E. , Balota , D. A. , Spieler , D. H. and Ferraro , F. R. 1999. Individual differences in information-processing rate and amount: Implications for group differences in response latency. Psychological Bulletin, 125: 777–799. [INFOTRIEVE][CROSSREF][CSA] [CrossRef], [PubMed], [Web of Science ®], [CSA]View all references, the results were analyzed in terms of raw reaction time (RT) data and using the z-score transformation to control for the presence of overadditivity effects. In terms of RTs, dyslexics showed a larger difference between words and nonwords (lexicality effect) and between short and long stimuli (length effect) than proficient readers. When data were transformed into z scores, only the group by length interaction remained significant while that with lexicality vanished. This pattern indicates that stimulus length has a specific role in Italian dyslexics’ reading deficit; in contrast, slowness in responding to nonwords was not specific but was interpreted as one aspect of dyslexics’ general inability to deal with alphabetical material (overadditivity effect).
Article
Frequentist methods are available for comparison of a patient's test score (or score difference) to a control or normative sample; these methods also provide a point estimate of the percentage of the population that would obtain a more extreme score (or score difference) and, for some problems, an accompanying interval estimate (i.e., confidence limits) on this percentage. In the present paper we develop a Bayesian approach to these problems. Despite the very different approaches, the Bayesian and frequentist methods yield equivalent point and interval estimates when (a) a case's score is compared to that of a control sample, and (b) when the raw (i.e., unstandardized) difference between a case's scores on two tasks are compared to the differences in controls. In contrast, the two approaches differ with regard to point estimates of the abnormality of the difference between a case's standardized scores. The Bayesian method for standardized differences has the advantages that (a) it can directly evaluate the probability that a control will obtain a more extreme difference score, (b) it appropriately incorporates error in estimating the standard deviations of the tasks from which the patient's difference score is derived, and (c) it provides a credible interval for the abnormality of the difference between an individual's standardized scores; this latter problem has failed to succumb to frequentist methods. Computer programs that implement the Bayesian methods are described and made available.
Human memory and medial temporal region of the brain. [Dissertation Abstracts International
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Progressive Matrices. Sets A, Ab, B: Board and Book Forms
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Beery-Buktenica " con i test supplementari Percezione Visiva e Coordinazione motoria. Firenze: Organizzazioni Speciali
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Wechsler D. Wais-R Wechsler Adult Intelligence Scale Revised. Firenze: Organizzazioni Speciali, 1997.