Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.

Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

Temporal evolution and strength of neural activity in parietal cortex during eye and hand movements.

The role of area 7a in eye-hand movement was studied by recording from individual neurons while monkeys performed 7 different tasks, aimed at assessing the relative influence of retinal, eye, and hand information on neural activity. Parietal cell activity was modulated by visuospatial signals about target location, as well as by information concerning eye and/or hand movement, and position. The highest activity was elicited when the hand moved to the fixation point. The population activities across different memory tasks showed common temporal peaks when aligned to the visual instruction (visuospatial peak) or Go signal (motor peak) for eye, hand, and coordinated eye-hand movement. The motor peak was higher for coordinated eye-hand movement, and it was absent in a No-Go task. Two activation maxima were also observed during visual reaching. They had the same latency of the visuospatial and motor peaks seen in the memory tasks. Therefore, area 7a seems to operate through a common neural mechanism underlying eye, hand, or combined eye-hand movement. This mechanism is revealed by invariant temporal activity profiles and is independent from the effector selected and from the presence or absence of a visible target during movement. For comparative purposes, we have studied the temporal evolution of the population activity in the superior parietal lobule (SPL) during the same reaching tasks and during a saccade task. In SPL, the population activity was characterized by a single peak, time locked to the Go signal for eye, hand, or combined eye-hand movement. As in IPL, the time of occurrence of this peak was effector independent. The population activity remained unchanged when the position of the eye changed, suggesting that SPL is mostly devoted to the hand motor behavior.

The over-representation of contralateral space in parietal cortex: a positive image of directional motor components of neglect?

The activity of single cells was recorded in behaving monkeys while they performed several eye-hand directional motor tasks. The results revealed that in parietal area 7a there exists a directional representation of eye and hand motor space that, contrary to that of superior parietal, premotor and motor cortex, is highly skewed toward the contralateral workspace. In man, the loss of this representation after parietal lesions might explain the emergence of the directional movement disorders of neglect. In fact, although unilateral neglect is consequence of damage to different brain structures, it is more common and enduring after right inferior parietal cortex lesions. Neglect patients ignore and avoid interacting with events occurring in the contralesional part of their physical and mental space. Current theories distinguish perceptual from motor components of neglect. One key feature of the latter is directional hypokinesia, an impaired representation of space for action, evident as difficulty to plan hand movements toward the contralesional part of egocentric space. An impairment of a similar nature is also observed for eye movements. In this study, we offer an interpretation of directional movement disorders of neglect from a physiological perspective, i.e. by focusing on the mechanisms underlying the representation of visuomotor space in parietal cortex.

A relational database for trial-based behavioral experiments.

We describe a relational database (RDB) structure suitable for trial-based experiments such as human psychophysics and neural recording studies in trained animals. An RDB is a collection of tables, each composed of columns. Some of the tables contain columns that reference specific columns of other tables. This referencing system links the tables to each other and makes it possible to extract any subset of the data with trivial commands. An equally important advantage of an RDB is that it imposes a consistent data format on applications that generate and analyze data. The result is a centralization and standardization of data storage that facilitates the pooling, cross-checking and re-analysis of data from various experiments. We present a robust RDB structure originally designed for neurophysiological data; however, it is abstract enough to accommodate data from a variety of trial-based experimental designs. Moreover, we demonstrated the advantages of this RDB structure and indicated its implementation in other laboratories.

The eye and the hand: neural mechanisms and network models for oculomanual coordination in parietal cortex.

The coordinated action of the eye and the hand is necessary for the successful performance of a large variety of motor tasks based on visual information. Although at the output level the neural control systems for the eye and the hand are largely segregated, in the parietal cortex of the macaque monkey there exist populations of neurons able to combine ocular and manual signals on the basis of their spatial congruence. An expression of this congruence is the clustering of eye- and hand-related preferred directions of these neurons into a restricted region of the workspace, defined as field of global tuning. This domain may represent a neural substrate for the early composition of commands for coordinated oculo-manual actions. Here we study two different prototypical network models integrating inputs about retinal target location, eye position and hand position. In the first one, we model the interaction of these different signals, as it occurs at the afferent level, in a feed-forward fashion. In the second model, we assume that recurrent interactions are responsible for their combination. Both models account surprisingly well for the experimentally observed global tuning fields of parietal neurons. When we compare them with the experimental findings, no significant difference emerges between the two. Experiments potentially able to discriminate between these models could be performed.

An integrated network for invariant visual detection and recognition.

We describe an architecture for invariant visual detection and recognition. Learning is performed in a single central module. The architecture makes use of a replica module consisting of copies of retinotopic layers of local features, with a particular design of inputs and outputs, that allows them to be primed either to attend to a particular location, or to attend to a particular object representation. In the former case the data at a selected location can be classified in the central module. In the latter case all instances of the selected object are detected in the field of view. The architecture is used to explain a number of psychophysical and physiological observations: object based attention, the different response time slopes of target detection among distractors, and observed attentional modulation of neuronal responses. We hypothesize that the organization of visual cortex in columns of neurons responding to the same feature at the same location may provide the copying architecture needed for translation invariance.