Closed-loop intracranial stimulation alters movement timing in humans.

BACKGROUND: A prime objective driving the recent development of human neural prosthetics is to stimulate neural circuits in a manner time-locked to ongoing brain activity. The human supplementary motor area (SMA) is a particularly useful target for this objective because it displays characteristic neural activity just prior to voluntary movement. OBJECTIVE: Here, we tested a method that detected activity in the human SMA related to impending movement and then delivered cortical stimulation with intracranial electrodes to influence the timing of movement. METHODS: We conducted experiments in nine patients with electrodes implanted for epilepsy localization: five patients with SMA electrodes and four control patients with electrodes outside the SMA. In the first experiment, electrocorticographic (ECoG) recordings were used to localize the electrode of interest during a task involving bimanual finger movements. In the second experiment, a real-time sense-and-stimulate (SAS) system was implemented that delivered an electrical stimulus when pre-movement gamma power exceeded a threshold. RESULTS: Stimulation based on real-time detection of this supra-threshold activity resulted in significant slowing of motor behavior in all of the cases where stimulation was carried out in the SMA patients but in none of the patients where stimulation was performed at the control site. CONCLUSIONS: The neurophysiological correlates of impending movement can be used to trigger a closed loop stimulation device and influence ongoing motor behavior in a manner imperceptible to the subject. This is the first report of a human closed loop system designed to alter movement using direct cortical recordings and direct stimulation.

Comparing Intelligence Quotient Change After Treatment With Proton Versus Photon Radiation Therapy for Pediatric Brain Tumors.

PURPOSE: Compared with photon radiation (XRT), proton beam radiation therapy (PBRT) reduces dose to normal tissues, which may lead to better neurocognitive outcomes. We compared change in intelligence quotient (IQ) over time in pediatric patients with brain tumors treated with PBRT versus XRT. PATIENTS AND METHODS: IQ scores were available for 150 patients (60 had received XRT, 90 had received PBRT). Linear mixed models examined change in IQ over time since radiation therapy (RT) by RT group, controlling for demographic/clinical characteristics. Craniospinal and focal RT subgroups were also examined. RESULTS: In the PBRT group, no change in IQ over time was identified (P = .130), whereas in the XRT group, IQ declined by 1.1 points per year (P = .004). IQ slopes did not differ between groups (P = .509). IQ was lower in the XRT group (by 8.7 points) versus the PBRT group (P = .011). In the craniospinal subgroup, IQ remained stable in both the PBRT (P = .203) and XRT groups (P = .060), and IQ slopes did not differ (P = .890). IQ was lower in the XRT group (by 12.5 points) versus the PBRT group (P = .004). In the focal subgroup, IQ scores remained stable in the PBRT group (P = .401) but declined significantly in the XRT group by 1.57 points per year (P = .026). IQ slopes did not differ between groups (P = .342). CONCLUSION: PBRT was not associated with IQ decline or impairment, yet IQ slopes did not differ between the PBRT and XRT groups. It remains unclear if PBRT results in clinically meaningful cognitive sparing that significantly exceeds that of modern XRT protocols. Additional long-term data are needed to fully understand the neurocognitive impact of PBRT in survivors of pediatric brain tumors.

Methotrexate administration directly into the fourth ventricle in children with malignant fourth ventricular brain tumors: a pilot clinical trial.

We hypothesize that chemotherapy can be safely administered directly into the fourth ventricle to treat recurrent malignant brain tumors in children. For the first time in humans, methotrexate was infused into the fourth ventricle in children with recurrent, malignant brain tumors. A catheter was surgically placed into the fourth ventricle and attached to a ventricular access device. Cerebrospinal fluid (CSF) flow was confirmed by CINE MRI postoperatively. Each cycle consisted of 4 consecutive daily methotrexate infusions (2 milligrams). Disease response was monitored with serial MRI scans and CSF cytologic analysis. Trough CSF methotrexate levels were sampled. Five patients (3 with medulloblastoma and 2 with ependymoma) received 18, 18, 12, 9, and 3 cycles, respectively. There were no serious adverse events or new neurological deficits attributed to methotrexate. Two additional enrolled patients were withdrawn prior to planned infusions due to rapid disease progression. Median serum methotrexate level 4 h after infusion was 0.04 µmol/L. Range was 0.02-0.13 µmol/L. Median trough CSF methotrexate level 24 h after infusion was 3.18 µmol/L (range 0.53-212.36 µmol/L). All three patients with medulloblastoma had partial response or stable disease until one patient had progressive disease after cycle 18. Both patients with ependymoma had progressive disease after 9 and 3 cycles, respectively. Low-dose methotrexate can be infused into the fourth ventricle without causing neurological toxicity. Some patients with recurrent medulloblastoma experience a beneficial anti-tumor effect both within the fourth ventricle and at distant sites.

Spatiotemporal flow of information in the early visual pathway.

The spatial components of a visual scene are processed neurally in a sequence of coarse features followed by fine features. This coarse-to-fine temporal stream was initially considered to be a cortical function, but has recently been demonstrated in the dorsal lateral geniculate nucleus. The goal of this study was to test the hypothesis that coarse-to-fine processing is present at earlier stages of visual processing in the retinal ganglion cells that supply lateral geniculate nucleus (LGN) neurons. To compare coarse-to-fine processing in the cat's visual system, we measured the visual responses of connected neuronal pairs from the retina and LGN, and separate populations of cells from each region. We found that coarse-to-fine processing was clearly present at the ganglion cell layer of the retina. Interestingly, peak and high-spatial-frequency cutoff responses were higher in the LGN than in the retina, indicating that there was a progressive cascade of coarse-to-fine information from the retina to the LGN to the visual cortex. The analysis of early visual pathway receptive field characteristics showed that the physiological response interplay between the center and surround regions was consistent with coarse-to-fine features and may provide a primary role in the underlying mechanism. Taken together, the results from this study provided a framework for understanding the emergence and refinement of coarse-to-fine processing in the visual system.

Development of orientation tuning in simple cells of primary visual cortex.

Orientation selectivity and its development are basic features of visual cortex. The original model of orientation selectivity proposes that elongated simple cell receptive fields are constructed from convergent input of an array of lateral geniculate nucleus neurons. However, orientation selectivity of simple cells in the visual cortex is generally greater than the linear contributions based on projections from spatial receptive field profiles. This implies that additional selectivity may arise from intracortical mechanisms. The hierarchical processing idea implies mainly linear connections, whereas cortical contributions are generally considered to be nonlinear. We have explored development of orientation selectivity in visual cortex with a focus on linear and nonlinear factors in a population of anesthetized 4-wk postnatal kittens and adult cats. Linear contributions are estimated from receptive field maps by which orientation tuning curves are generated and bandwidth is quantified. Nonlinear components are estimated as the magnitude of the power function relationship between responses measured from drifting sinusoidal gratings and those predicted from the spatial receptive field. Measured bandwidths for kittens are slightly larger than those in adults, whereas predicted bandwidths are substantially broader. These results suggest that relatively strong nonlinearities in early postnatal stages are substantially involved in the development of orientation tuning in visual cortex.

Rapid plasticity of visual responses in the adult lateral geniculate nucleus.

Compared to the developing visual system, where neuronal plasticity has been well characterized at multiple levels, little is known about plasticity in the adult, particularly within subcortical structures. We made intraocular injections of 2-amino-4-phosphonobutyric acid (APB) in adult cats to block visual responses in On-center retinal ganglion cells and examined the consequences on visual responses in the lateral geniculate nucleus (LGN) of the thalamus. In contrast to current views of retinogeniculate organization, which hold that On-center LGN neurons should become silent with APB, we find that ∼50% of On-center neurons rapidly develop Off-center responses. The time course of these emergent responses and the actions of APB in the retina indicate the plasticity occurs within the LGN. These results suggest there is greater divergence of retinogeniculate connections than previously recognized and that functionally silent, nonspecific retinal inputs can serve as a substrate for rapid plasticity in the adult.

Adaptation changes stereoscopic depth selectivity in visual cortex.

Exposure to specific visual stimuli causes a reduction in sensitivity to similar subsequent stimulation. This adaptation effect is observed behaviorally and for neurons in the primary visual cortex. Here, we explore the effects of adaptation on neurons that encode binocular depth discrimination in the cat's primary visual cortex. Our results show that neuronal preference for binocular depth is altered selectively with appropriate adaptation. At the preferred depth, adaptation causes substantial suppression of subsequent responses. Near the preferred depth, the same procedure causes a shift in depth preference. At the null depth, adaptation has little effect on binocular depth coding. These results demonstrate that prior exposure can change the depth selectivity of binocular neurons. The findings are relevant to the theoretical treatment of binocular depth processing. Specifically, the prevailing notion of binocular depth encoding based on the energy model requires modification.

A comparison of visual responses in the lateral geniculate nucleus of alert and anaesthetized macaque monkeys.

Despite the increasing use of alert animals for studies aimed at understanding visual processing in the cerebral cortex, relatively little attention has been focused on quantifying the response properties of neurons that provide input to the cortex. Here, we examine the response properties of neurons in the lateral geniculate nucleus (LGN) of the thalamus in the alert macaque monkey and compare these responses to those in the anaesthetized animal. Compared to the anaesthetized animal, we show that magnocellular and parvocellular neurons in the alert animal respond to visual stimuli with significantly higher firing rates. This increase in responsiveness is not accompanied by a change in the shape of neuronal contrast response functions or the strength of centre­surround antagonism; however, it is accompanied by an increased ability of neurons to follow stimuli drifting at higher spatial and temporal frequencies.

Potential influences on mathematical difficulties in children and adolescents with neurofibromatosis, type 1.

Neurofibromatosis, type 1 (NF-1) is a common genetic disorder affecting 1 in 3,500-4,000 individuals in the world. Mutations of the NF-1 gene produce a myriad of physical, medical, and psychological manifestations. Although there is a very high degree of variability in the manifestations between individuals with NF-1, the majority of children and adolescents with NF-1 encounter difficulties that negatively impact their educational attainment. NF-1 is associated with a very high incidence of cognitive deficits and learning disability, sometimes including mathematical learning disabilities (MLD). A number of possible inter-related etiologies for MLD specific to children and adolescents with NF-1 are discussed, including the high incidence of attention deficit hyperactivity disorder, visual spatial impairment, morphological and functional brain abnormalities. Thus NF-1 exemplifies the wide ranging sources of potential influences on mathematical learning and MLD.

Psychosocial support of the pediatric cancer patient: lessons learned over the past 50 years.

Advances in pediatric cancer treatment over the past 50 years have dramatically improved survival rates. Once considered almost uniformly fatal, pediatric cancer's overall survival rates now approach 85%. Formerly, little psychosocial support existed for the child with cancer other than that provided by nurses and family. The prospect for long-term survival was so remote that plans for the future (eg, school, social relationships, late effects of treatment, and emotional adjustment) were abandoned. As the survival rate for children with cancer improved, so did the need for and quality of psychosocial care, largely because of hope for a cure. Today children with cancer benefit from comprehensive behavioral pediatric psychosocial support programs in psychiatry, psychology, neuropsychology, child life, education (school), creative arts, chaplaincy, social work, and career and vocational counseling. Pediatric psycho-oncology research has provided insights into clinical care and the psychosocial adaptation of children and families to cancer treatment and survivorship.

Preventing neurocognitive late effects in childhood cancer survivors.

Neurocognitive late effects are common sequelae of cancer in children, especially in those who have undergone treatment for brain tumors or in those receiving prophylactic cranial radiation therapy to treat leukemia. Neurocognitive morbidity in attention, executive functioning, processing speed, working memory, and memory frequently occurs and contributes to declines in intellectual and academic abilities. Oncologists are faced with the challenge of using the most effective, often the most intense, therapy to achieve the primary goal of medical success, balanced with the desire to prevent adverse late effects. Not all children with similar diagnoses and treatment have identical neurocognitive outcomes; some do very poorly and some do well. Attention now turns to the reliable prediction of risk for poor outcomes and then, using risk-adapted therapy, to preserve neurocognitive function. Prevention of late effects through rehabilitative strategies, continuation of school, and pharmacotherapy will be explored.

Social, emotional, and behavioral functioning of children with NF1.

Children with neurofibromatosis type 1 (NF1) can have varying degrees of cognitive impairment, and are at risk for social, emotional, and behavioral dysfunction. We undertook an evaluation of social, emotional, and behavioral functioning of youth with NF1 and peers from multiple perspectives. We hypothesized that children with NF1 would have more psychosocial difficulties, which would be positively associated with neurological involvement. We compared 58 children with NF1, ages 7-15, with comparison classroom peers, classmates who were same race/gender and closest date of birth. Peer relationships, emotional well-being, and behavior were evaluated from multiple perspectives in multiple settings. Results showed that teachers perceived children with NF1 as more prosocial (i.e., polite, helpful to others). Teachers and peers viewed children with NF1 as displaying less leadership behavior and as more socially sensitive-isolated (i.e., often left out, trouble making friends). Children with NF1 had fewer friendships and were less well liked by peers. Mothers and fathers reported more problems with social functioning among children with NF1. Few group differences in emotional well-being and behavior were identified according to child and father report. However, mothers perceived children with NF1 to have more emotional problems relative to comparison peers, predominantly among older children. Neurological involvement was significantly related to psychosocial problems. We conclude that children with NF1 are frequently socially isolated and rejected by peers; and that greater neurological involvement is associated with more emotional problems. Central nervous system involvement appears to play a key role in identifying children at risk for problems with friendships, social acceptance, and emotional functioning (i.e., depression).

Orientation tuning, but not direction selectivity, is invariant to temporal frequency in primary visual cortex.

The activity of neurons in primary visual cortex is influenced by the orientation, contrast, and temporal frequency of a visual stimulus. This raises the question of how these stimulus properties interact to shape neuronal responses. While past studies have shown that the bandwidth of orientation tuning is invariant to stimulus contrast, the influence of temporal frequency on orientation-tuning bandwidth is unknown. Here, we investigate the influence of temporal frequency on orientation tuning and direction selectivity in area 17 of ferret visual cortex. For both simple cells and complex cells, measures of orientation-tuning bandwidth (half-width at half-maximum response) are approximately 20-25 degrees across a wide range of temporal frequencies. Thus cortical neurons display temporal-frequency invariant orientation tuning. In contrast, direction selectivity is typically reduced, and occasionally reverses, at nonpreferred temporal frequencies. These results show that the mechanisms contributing to the generation of orientation tuning and direction selectivity are differentially affected by the temporal frequency of a visual stimulus and support the notion that stability of orientation tuning is an important aspect of visual processing.

Neurocognitive outcomes in survivors of childhood cancer.

OBJECTIVE: s To review issues associated with neurocognitive outcome in survivors of pediatric cancer. Recommendations are made for future research directions. METHODS: A large body of literature pertaining to neurocognitive outcome in cancer survivors was reviewed. Brain development and methodological issues that provide challenges to conducting meaningful research in cancer outcomes also are discussed. RESULTS: Neurotoxic agents used in some cancer therapies produce permanent neurocognitive sequelae, especially in very young children. CONCLUSIONS: The state of neurocognitive research for pediatric cancer survivors needs to move beyond empirical studies of neurocognitive sequelae to research that will identify individual patients at risk for neurocognitive morbidity.

Functional MRI of visual-spatial processing in neurofibromatosis, type I.

Visual-spatial impairment and neuroanatomical abnormalities are considered hallmark features of neurofibromatosis, type I (NF-I). Numerous studies have demonstrated visual-spatial deficits in children with NF-I, but few relations between these deficits and neuroanatomical abnormalities have been identified. We compared the functional neuroanatomy of cerebral regions involved in the spatial transformation of alphanumeric stimuli in individuals with NF-I and healthy control participants using functional magnetic resonance imaging (fMRI). Given the prevalence of visual pathway abnormalities and visual-spatial deficits in NF-I, we hypothesized that less neuronal hemodynamic activity would be found in occipital and parietal cortices in this group compared with controls. However, NF-I participants relied to a greater degree than controls on posterior cortex (including occipital, parietal, and middle temporal cortices) relative to lateral and inferior frontal regions during visual-spatial analysis. This pattern was significantly related to their behavioral performance on the fMRI task, which in turn was also positively correlated with reading scores. These findings support evidence of frontal cortical anomalies in NF-I and may provide a pathophysiological basis for cognitive deficits in NF-I.

Functional magnetic resonance imaging of phonologic processing in neurofibromatosis 1.

Neurofibromatosis 1 is associated with reading disabilities, but few associations between neuroanatomic abnormalities and reading problems have been found. We examined the neuronal bases for phonologic processing, a core component of learning to read, in 15 individuals with neurofibromatosis 1 and 15 controls using functional magnetic resonance imaging (MRI). Our results revealed differential use of inferior and dorsolateral prefrontal cortical areas relative to posterior (temporal, parietal, and occipital) cortices for participants with neurofibromatosis 1 compared with controls during phonologic (rhyme) decisions. In addition, similar to previous brain imaging studies of reading deficits in the general population, poorer performance on one of the phonologic decision tasks was associated with increased signal change in the right superior temporal gyrus for the neurofibromatosis 1 group. Behavioral performance on the functional MRI tasks was related to academic reading measures for the neurofibromatosis 1 group. The differential patterns of functional connectivity observed here lend support to previous morphologic studies that suggested inferior frontal and superior temporal areas to be important mediators of reading and language development in neurofibromatosis 1.

Visual-spatial performance deficits in children with neurofibromatosis type-1.

Neurofibromatosis type-1 (NF1) is a common genetic disorder associated with a variety of medical complications, cognitive impairments, and behavioral problems including a high incidence of Attention Deficit Hyperactivity Disorder (ADHD). The current study examined the hypotheses that deficits in visual-spatial/motor abilities enable one to discriminate and classify children with NF1 (n = 101) compared to control children (n = 37), beyond effects secondary to parent reported ADHD symptomology. Discriminant analysis showed a multivariate combination of visual-spatial/motor ability tests (Judgment of Line Orientation, Block Design subtest of the WISC-III, Recognition-Discrimination Test, Beery Visual-Motor Integration Test) to be a significant predictor of NF1 diagnostic status (P = 0.0000004; canonical R(2) = 0.2306). A significantly greater degree of ADHD behavior was found in the NF1 group, and a discriminant analysis using ADHD residualized visual-spatial motor scores indicated that the combination of tests continued to be a significant predictor of group membership after the level of ADHD behavior was controlled (P = 0.00002 and a canonical R(2) = 0.1818). This combination of tests proved to be a strong discriminator of NF1. It correctly identified 90% of individuals with the diagnosis, and may be useful to educators to provide assistance and alternatives to minimize the impact of learning problems in those with either known or suspected NF1.