From competition to cooperation: Visual neglect across the hemispheres.

Visuospatial neglect is a frequent and disabling consequence of injuries to the right hemisphere. Patients with neglect show signs of impaired attention for left-sided events, which depends on dysfunction of fronto-parietal networks. After unilateral injury, such as stroke, these networks and their contralateral homologs can reorganize following multiple potential trajectories, which can be either adaptive or maladaptive. This article presents possible factors influencing the profile of evolution of neglect towards recovery or chronicity, and highlights potential mechanisms that may constrain these processes in time and space. The integrity of white matter pathways within and between the hemisphere appears to pose crucial connectivity constraints for compensatory brain plasticity from remote brain regions. Specifically, the availability of a sufficient degree of inter-hemispheric connectivity might be critical to shift the role of the undamaged left hemisphere in spatial neglect, from exerting maladaptive effects, to promoting compensatory activity.

Visual and motor neglect: Clinical and neurocognitive aspects.

Attention allows us to prioritize the processing of external information according to our goals, but also to cope with sudden, unforeseen events. Attention processes rely on the coordinated activity of large-scale brain networks. At the cortical level, these systems are mainly organized in fronto-parietal networks, with functional and anatomical asymmetries in favor of the right hemisphere. Dysfunction of these right-lateralized networks often produce severe deficit of spatial attention, such as visual neglect. Other brain-damaged patients avoid moving the limbs contralateral to their brain lesion, even in the absence of sensorimotor deficits (motor neglect). This paper first summarizes past and current evidence on brain networks of attention; then, it presents clinical and experimental findings on visual and motor neglect, and on the possible mechanisms of clinical recovery.

Spermatogonial kinetics in humans.

The human spermatogonial compartment is essential for daily production of millions of sperm. Despite this crucial role, the molecular signature, kinetic behavior and regulation of human spermatogonia are poorly understood. Using human testis biopsies with normal spermatogenesis and by studying marker protein expression, we have identified for the first time different subpopulations of spermatogonia. MAGE-A4 marks all spermatogonia, KIT marks all B spermatogonia and UCLH1 all Apale-dark (Ap-d) spermatogonia. We suggest that at the start of the spermatogenic lineage there are Ap-d spermatogonia that are GFRA1High, likely including the spermatogonial stem cells. Next, UTF1 becomes expressed, cells become quiescent and GFRA1 expression decreases. Finally, GFRA1 expression is lost and subsequently cells differentiate into B spermatogonia, losing UTF1 and acquiring KIT expression. Strikingly, most human Ap-d spermatogonia are out of the cell cycle and even differentiating type B spermatogonial proliferation is restricted. A novel scheme for human spermatogonial development is proposed that will facilitate further research in this field, the understanding of cases of infertility and the development of methods to increase sperm output.

Auditory spatial cueing reduces neglect after right-hemispheric stroke: A proof of concept study.

Spatial neglect after right-hemispheric stroke, characterized by the failure to attend or respond to the contralesional space, is a strong negative outcome predictor. Neglect is a supramodal syndrome affecting not only the visual but also the auditory modality. Preliminary studies used this audio-visual cross-modal effect to show short-lasting effects on attention towards the neglected space. The aim of the present study was to introduce a new technique of auditory stimulation combining the unspecific effect of music (i.e., patients choose their preferred music) with the effects of auditory spatial cueing (i.e., the music is presented dynamically as moving from right to left). The effect of this new auditory stimulation technique was investigated in two proof-of-concept experiments using repeated-measures, cross-over designs including 21 patients with visual neglect after a first right-hemispheric stroke. In Experiment I (n = 9), neglect patients showed a significantly larger improvement in Letter Cancellation after listening to preferred music with than without auditory spatial cueing. After granting the feasibility of this new auditory stimulation technique, we investigated the long-term aftereffects in Experiment II (n = 12). Herefore, we used video-oculography during Free Visual Exploration, a sensitive and reliable tool to assess spatial attention over time. Listening to music with auditory spatialcueing - as compared to music without auditory spatialcueing - significantly improved neglect severity in terms of visual exploration behaviour for up to 3h. A voxel-based-lesion-symptom mapping analysis over all patients revealed that the response variability in listening to music with auditory spatial cueing is determined by the integrity of the right inferior parietal lobule, the second branch of the superior longitudinal fascicle, and parieto-parietal callosal fibres. Our study shows that listening to music with auditory spatial cueing significantly reduces neglect severity and has the potential to be used as an add-on in the neurorehabilitation of neglect.

DTI-MR tractography of white matter damage in stroke patients with neglect.

Left visual neglect is a dramatic neurological condition that impairs awareness of left-sided events. Neglect has been classically reported after strokes in the territory of the right middle cerebral artery. However, the precise lesional correlates of neglect within this territory remain discussed. Recent evidence strongly suggests an implication of dysfunction of large-scale perisylvian networks in chronic neglect, but the quantitative relationships between neglect signs and damage to white matter (WM) tracts have never been explored. In this prospective study, we used diffusion tensor imaging (DTI) tractography in twelve patients with a vascular stroke in the right hemisphere. Six of these patients showed signs of neglect. Nonparametric voxel-based comparisons between neglect and controls on fractional anisotropy maps revealed clusters in the perisylvian WM and in the external capsule. Individual DTI tractography identified specific disconnections of the fronto-parietal and fronto-occipital pathways in the neglect group. Voxel-based correlation statistics highlighted correlations between patients' performance on two visual search tasks and damage to WM clusters. These clusters were located in the anterior limb of the internal capsule and in the WM underlying the inferior frontal gyrus, along the trajectory of the anterior segment of the arcuate fasciculus (asAF). These results indicate that chronic visual neglect can result from, and correlate with, damage to fronto-parietal connections in the right hemisphere, within large-scale cortical networks important for orienting of spatial attention, arousal and spatial working memory.

[Presentation of an assessment battery for visual mental imagery and visual perception]. / Normalisation d'une batterie d'évaluation de l'imagerie mentale visuelle et de la perception visuelle.

INTRODUCTION: The relationship between visual perception and visual mental imagery are at the center of a lively theoretical debate between those postulating common neurocognitive processes between perception and imagery and those who emphasize the differences between these two entities. Neuropsychology can make an important contribution to this debate, by assessing associations and dissociations between perceptual and imaginal deficits in patients with brain damage. However, currently there is no standardized test battery available for such assessments. MATERIAL AND METHODS: Here we present a battery of paper-and-pencil tests assessing different domains of visual mental imagery and visual perception abilities: object form and color, animals, orthographic material, numbers, faces, and space. We also explored the effects of age, educational level and gender on performance on a group of 103 participants free of neurological damage. RESULTS: The battery includes two parts: one composed of 14 tests assessing mental imagery and the second part composed of eight tests assessing the abilities of visual perception. We calculated the correlations between the tests, and found that, with the exception of orthographic material, there were generally poor correlations between imagery and perceptual tests. CONCLUSION: This result seems inconsistent with hypotheses postulating a strict correspondence between perceptual and imagery abilities.

Brain networks of spatial awareness: evidence from diffusion tensor imaging tractography.

Left unilateral neglect, a dramatic condition which impairs awareness of left-sided events, has been classically reported after right hemisphere cortical lesions involving the inferior parietal region. More recently, the involvement of long range white matter tracts has been highlighted, consistent with the idea that awareness of events occurring in space depends on the coordinated activity of anatomically distributed brain regions. Damage to the superior longitudinal fasciculus (SLF), linking parietal to frontal cortical regions, or to the inferior longitudinal fasciculus (ILF), connecting occipital and temporal lobes, has been described in neglect patients. In this study, four right-handed patients with right hemisphere strokes underwent a high definition anatomical MRI with diffusion tensor imaging (DTI) sequences and a pencil and paper neglect battery of tests. We used DTI tractography to visualise the SLF, ILF and the inferior fronto-occipital fasciculus (IFOF), a pathway running the depth of the temporal lobe, not hitherto associated with neglect. Two patients with cortical involvement of the inferior parietal and superior temporal regions, but intact and symmetrical fasciculi, showed no signs of neglect. The other two patients with signs of left neglect had superficial damage to the inferior parietal cortex and white matter damage involving the IFOF. These findings suggest that superficial damage to the inferior parietal cortex per se may not be sufficient to produce visual neglect. In some cases, a lesion to the direct connections between ventral occipital and frontal regions (ie, IFOF) may contribute to the manifestation of neglect by impairing the top down modulation of visual areas from the frontal cortex.

[Unilateral spatial neglect: 30 years of research, discoveries, hope, and (especially) questions]. / La négligence spatiale unilatérale : trente ans de recherches, de découvertes, d'espoirs et (surtout) de questions.

Unilateral spatial neglect (USN) was defined 30 years ago as "a failure to report, respond, or orient to stimuli that are presented contralateral to a brain lesion, provided that this failure is not due to elementary sensory or motor disorders" by Heilman and Valenstein (1979). Even though this definition still holds, the last 30 years have been characterized by a profusion of clinical descriptions, neuroanatomical investigations and theoretical models of neglect. This article summarizes the wealth of neuroanatomical, clinical and experimental data concerning USN, by focusing on attentional and spatial deficits. Finally, some perspectives on neglect research are outlined.

Secondary solid cancer following hematopoietic cell transplantation in patients with thalassemia major.

Hematopoietic cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers (SSCs). The aim of this retrospective study was to compare the incidence of SSC in a monocentric cohort of thalassemia major (TM) patients (n=122) who received HCT versus an hematopoietic cell donor monocentric cohort (n=122) and versus a large multicenter cohort of age- and sex-matched TM patients (n=244) who received conventional therapy. With a median follow-up of 24 years, 8 transplanted patients were diagnosed with SSC at a median of 18 years after HCT and at a median age of 33 years. Three patients died of cancer progression and 5 are living after a follow-up ranging from 10 months to 16 years after SSC diagnosis. The 30-year cumulative incidence of developing SSC was 13.24%. The occurrence of solid cancers in the hematopoietic cell donor cohort was limited to only one case for a significantly lower cumulative incidence (3.23%, P=0.02) and to 3 cases in the cohort of nontransplant patients for a significantly lower cumulative incidence (1.32%, P=0.005). This study shows that the magnitude of increased risk of SST is fourfold to sixfold for patients treated with HCT as compared with hematopoietic cell donors and nontransplant patients.

Efficacy of caspofungin as secondary prophylaxis in patients undergoing allogeneic stem cell transplantation with prior pulmonary and/or systemic fungal infection.

Transplanted patients with a history of invasive fungal infection (IFI) are at high risk of developing relapse and fatal complications. Eighteen patients affected by hematological malignancies and a previous IFI were submitted to allogeneic stem cell transplantation, using Caspofungin as a secondary prophylaxis. Patients had a probable or proven fungal infection and 16 had a pulmonary localization. No side effects were recorded during treatment with Caspofungin. Compared to pre-transplant evaluation, stability or improvement of the previous IFI was observed in 16 of the 18 patients at day 30, in 13 of the 15 evaluable patients at day 180 and in 11 of the 11 evaluable patients at day 360 post transplant. In particular, all the six patients with a proven fungal infection were alive, with a stable or improved IFI after 1 year from transplant. At a maximum follow-up of 31 months, eight patients died for disease progression or transplant-related complications, but only two had evidence of fungal progression. Secondary prophylaxis with Caspofungin may represent a suitable approach to limit IFI relapse or progression, allowing patients with hematological malignancies to adhere to the planned therapeutic program.

[Unilateral spatial neglect: a dramatic but often neglected consequence of right hemisphere damage]. / Négligence spatiale unilatérale: une conséquence dramatique mais souvent négligée des lésions de l'hémisphère droit.

INTRODUCTION: Unilateral Spatial Neglect (USN) is a common consequence of right brain damage. In the most severe cases, behavioral signs of USN can last several years and compromise patients' autonomy and social rehabilitation. These clinical facts stress the need for reliable procedures of diagnosis and rehabilitation. STATE OF THE ART: The last 3 decades have witnessed an explosion of studies on USN, which raises issues related to complex cognitive activities such as mental representation, spatial attention and consciousness. USN is probably a heterogeneous syndrome, but some of its underlying mechanisms might be understood as an association of disorders of spatial attention. A bias of automatic orienting towards right-sided objects seems typical of left USN. Afterwards, patients find it difficult to disengage their attention in order to explore the rest of the visual scene. Neglected objects are sometimes processed in an "implicit" way. PERSPECTIVES: The development of behavioural paradigms and of neuroimaging techniques and their application to the study of USN has advanced our understanding of the functional mechanisms of attention and spatial awareness, as well as of their neural bases. A number of new procedures for rehabilitation have recently been proposed. CONCLUSION: The present review describes the clinical presentation of USN, its anatomical basis and some of possible accounts of different aspects of neglect behavior. Results of computer simulations and of rehabilitation techniques are also presented with implications for the functioning of normal neurocognitive systems.

Pregnancy outcome following hematopoietic cell transplantation for thalassemia major.

The aim of this study was to investigate the methods of conception and delivery, as well as the course and outcome of 42 pregnancies occurring in 15 female patients (27 pregnancies) and partners of 8 male patients (15 pregnancies) with ß-thalassemia major who were successfully treated with allogeneic hematopoietic cell transplantation (HCT). Most pregnancies (n=21) were achieved with spontaneous conception in female patients. There were two miscarriages. Five pregnancies were late preterm. Delivery was vaginal in 4 cases and by caesarean section in 18. Overall, 22 term pregnancies resulted in successful deliveries of 23 neonates. Two of 23 neonates were symmetrical small for gestational age / intrauterine growth restriction. All 15 pregnancies that occurred in partners of men who received an allogeneic HCT were achieved with spontaneous conception. No miscarriage was observed. Overall, 14 term pregnancies resulted in successful deliveries of 14 live-born singletons. Delivery was vaginal in nine cases and by caesarean section in five. All infants were full-term. Many patients with ß-thalassemia major who received an allogeneic HCT retained or recovered their fertility after transplant. In these patients, pregnancy has been a practical and safe possibility and usually had a favorable outcome as in the normal population.

Differential actigraphy for monitoring asymmetry in upper limb motor activities.

Most applications of accelerometry-based actigraphy require a single sensor, properly located onto the body, to estimate, for example, the level of activity or the energy expenditure. Some approaches adopt a multi-sensor setup to improve those analyses or to classify different types of activity. The specific case of two symmetrically placed actigraphs allowing, by some kind of differential analysis, for the assessment of asymmetric motor behaviors, has been considered in relatively few studies. This article presents a novel method for differential actigraphy, which requires the synchronized measurements of two triaxial accelerometers (programmable eZ430-Chronos, Texas Instruments, USA) placed symmetrically on both wrists. The method involved the definition of a robust epoch-related activity index and its implementation on-board the adopted programmable platform. Finally, the activity recordings from both sensors allowed us to define a novel asymmetry index AR24 h ranging from -100% (only the left arm moves) to +100% (only the right arm moves) with null value marking a perfect symmetrical behavior. The accuracy of the AR24 h index was 1.3%. Round-the-clock monitoring on 31 healthy participants (20-79 years old, 10 left handed) provided for the AR24 h reference data (range -5% to 21%) and a fairly good correlation to the clinical handedness index (r = 0.66, p < 0.001). A subset of 20 participants repeated the monitoring one week apart evidencing an excellent test-retest reliability (r = 0.70, p < 0.001). Such figures support future applications of the methodology for the study of pathologies involving motor asymmetries, such as in patients with motor hemisyndromes and, in general, for those subjects for whom a quantification of the asymmetry in daily motor performances is required to complement laboratory tests.

Second allogeneic bone marrow transplantation in acute leukemia: a multicenter study from the Gruppo Italiano Trapianto Di Midollo Osseo (GITMO).

Thirty-eight second allogeneic bone marrow transplants (BMT) for acute leukemia relapsed after first BMT were performed in 13 Italian centers between 1987 and 1994. Twenty-one patients had acute myelogenous leukemia (AML), 17 acute lymphoblastic leukemia (ALL); at second BMT 24 patients were in complete remission (CR) and 14 in relapse. The median time to relapse after first BMT was 10 months (range 1-70). Grade II or greater acute graft-versus-host disease (GVHD) after second transplant occurred in 34.2% of patients and a chronic GVHD in 31.5% of patients. Twenty-four patients died: seven from early transplant-related mortality (TRM), 13 from relapse and four from late toxicity. As of 31 July 1996, at a median follow-up of 47 months (range 22-85), there are 14 survivors. The three-year probability of TRM, relapse and event-free survival (EFS) is 28%, 40% and 42% respectively. In 20 of 27 evaluable patients, remission duration after second BMT was longer than after the first BMT. A diagnosis of AML was correlated with a better outcome. These data support the usefulness of second allograft in selected patients with AML relapsing after a first BMT.

Haploidentical, G-CSF-primed, unmanipulated bone marrow transplantation for patients with high-risk hematological malignancies: an update.

Ninety-seven patients affected by high-risk hematological malignancies underwent G-CSF primed, unmanipulated bone marrow (BM) transplantation from a related, haploidentical donor. All patients were prepared with an identical conditioning regimen including Thiotepa, Busilvex, Fludarabine (TBF) and antithymocyte globulin given at myeloablative (MAC = 68) or reduced (reduced intensity conditioning (RIC) = 29) dose intensity and received the same GvHD prophylaxis consisting of the combination of methotrexate, cyclosporine, mycofenolate-mofetil and basiliximab. Patients were transplanted in 1st or 2nd CR (early phase: n = 60) or in > 2nd CR or active disease (advanced phase: n = 37). With a median time of 21 days (range 12-38 days), the cumulative incidence (CI) of neutrophil engraftment was 94 ± 3%. The 100-day CI of III-IV grade acute GvHD and the 2-year CI of extensive chronic GvHD were 9 ± 3% and 12 ± 4%, respectively. Overall, at a median follow-up of 2.2 years (range 0.3-5.6), 44 out of 97 (45%) patients are alive in CR. The 5-year probability of overall survival (OS) and disease-free survival (DFS) for patients in early and advanced phase was 53 ± 7 vs 24 ± 8% (P = 0.006) and 48 ± 7 vs 22 ± 8% (P = 0.01), respectively. By comparing MAC with RIC patient groups, the transplant-related mortality was equivalent (36 ± 6 vs 28 ± 9%) while the relapse risk was lower for the MAC patients (22 ± 6 vs 45 ± 11%), who showed higher OS (48 ± 7 vs 29 ± 10%) and DFS (43 ± 7 vs 26 ± 10%). However, all these differences did not reach a statistical significance. In multivariate analysis, diagnosis and recipient age were significant factors for OS and DFS. In conclusion, this analysis confirms, on a longer follow-up and higher number of patients, our previous encouraging results obtained by using MAC and RIC TBF regimen as conditioning for G-CSF primed, unmanipulated BM transplantation from related, haploidentical donor in patients with high-risk hematological malignancies, lacking an HLA-identical sibling or unrelated donor and in need to be urgently transplanted.

Left unilateral neglect or right hyperattention?

BACKGROUND: Contradictory interpretations of left unilateral neglect suggest that it reflects either decreased attention toward the left or increased attention toward the right. According to the right-hyperattention postulate, increasing severity of neglect should result from an increasingly stronger bias toward the right. Thus, response times to right-sided targets should become progressively faster as neglect increases in severity across patients. The left-hypoattention postulate predicts that as neglect increases, progressively less-attentional resources are deployed in both hemispaces. Thus, response times to right targets should progressively increase with increasing neglect. METHODS: We analyzed the distribution of manual response times to left- and right-sided targets in 24 patients with right hemisphere lesions and varying degrees of left neglect. RESULTS: Not only the responses to left targets but also those to right targets became progressively slower as neglect increased, consistent with the hypoattention account. However, the two regression lines were not parallel. With increasing neglect, responses to left targets increased more steeply than those to right targets did. CONCLUSIONS: A rightward attentional bias is present in patients with left neglect, together with left hypoattention. However, this rightward bias is one of defective, and not enhanced, attention.

The relationship between visuospatial and representational neglect.

Using a quantitative measure, we analyzed the relationship between visuospatial and representational neglect in right- and left-brain-damaged patients and found signs of representational neglect only in right-brain-damaged patients. Although representational neglect was always associated with visuospatial neglect, suggesting that the two forms share a common underlying mechanism, the most frequent finding in right-brain--damaged patients was that of visuospatial neglect in isolation. A strong influence of the phenomenon of attentional attraction toward space ipsilateral to the lesion in visuospatial, as opposed to imaginal, tasks can account for this finding.

Disruption of residual reading capacity in a pure alexic patient after a mirror-image right-hemispheric lesion.

A 74-year-old woman became a letter-by-letter reader after the occurrence of a left occipito-temporal hematoma. Seven months later, she suffered a second, mirror-image hematoma in the right hemisphere. After this second lesion, her residual reading capacity deteriorated dramatically in terms of both accuracy and reading latencies for words and isolated letters. Our findings support the hypothesis that the right hemisphere contributes to the residual reading capacities of pure alexic patients.

Right-side neglect in Alzheimer's disease.

Unilateral neglect--the inability to pay attention to events occurring on one side of space--usually occurs for left-side events after focal right-hemisphere damage. We report a 73-year-old woman with probable AD and no evidence of focal brain lesions who showed signs of right-side neglect and extinction. Neglect was more severe after 1 year. Neuroimaging techniques demonstrated an asymmetry of cortical involvement, with cortical atrophy and hypoperfusion predominant in the left posterior regions. Unilateral neglect should be assessed systematically in AD.