Magnus K. O. Burstedt

Control of grasp stability during pronation and supination movements

Abstract We analyzed the control of grasp stability during a major manipulative function of the human hand: rotation of a grasped object by pronation and supination movement. We investigated the regulation of grip forces used to stabilize an object held by a precision grip between the thumb and index finger when subjects rotated it around a horizontal axis. Because the center of mass was located distal to the grip axis joining the fingertips, destabilizing torque tangential to the grasp surfaces developed when the grip axis rotated relative to the field of gravity. The torque load was maximal when the grip axis was horizontal and minimal when it was vertical. An instrumented test object, with a mass distribution that resulted in substantial changes in torque load during the rotation task, measured forces and torques applied by the digits. The mass distribution of the object was unpredictably changed between trials. The grip force required to stabilize the object increased directly with increasing torque load. Importantly, the grip force used by the subjects also changed in proportion to the torque load such that subjects always employed adequate safety margins against rotational slips, i.e., some 20–40% of the grip force. Rather than driven by sensory feedback pertaining to the torque load, the changes in grip force were generated as an integral part of the motor commands that accounted for the rotation movement. Subjects changed the grip force in parallel with, or even slightly ahead of, the rotation movement, whereas grip force responses elicited by externally imposed torque load changes were markedly delayed. Moreover, blocking sensory information from the digits did not appreciably change the coordination between movement and grip force. We thus conclude that the grip force was controlled by feedforward rather than by feedback mechanisms. These feedforward mechanisms would thus predict the consequences of the rotation movement in terms of changes in fingertip loads when the orientation of the grip axis changed in the field of gravity. Changes in the object’s center of mass between trials resulted in a parametric scaling of the motor commands prior to their execution. This finding suggests that the sensorimotor memories used in manipulation to adapt the motor output for the physical properties of environmental objects also encompass information related to an object’s center of mass. This information was obtained by somatosensory cues when subjects initially grasped the object with the grip axis vertical, i.e., during minimum tangential torque load.

Coordination of fingertip forces during human manipulation can emerge from independent neural networks controlling each engaged digit

Abstract We investigated the coordination of fingertip forces in subjects who lifted an object (i) using the index finger and thumb of their right hand, (ii) using their left and right index fingers, and (iii) cooperatively with another subject using the right index finger. The forces applied normal and tangential to the two parallel grip surfaces of the test object and the vertical movement of the object were recorded. The friction between the object and the digits was varied independently at each surface between blocks of trials by changing the materials covering the grip surfaces. The object’s weight and surface materials were held constant across consecutive trials. The performance was remarkably similar whether the task was shared by two subjects or carried out unimanually or bimanually by a single subject. The local friction was the main factor determining the normal:tangential force ratio employed at each digit-object interface. Irrespective of grasp configuration, the subjects adapted the force ratios to the local frictional conditions such that they maintained adequate safety margins against slips at each of the engaged digits during the various phases of the lifting task. Importantly, the observed force adjustments were not obligatory mechanical consequences of the task. In all three grasp configurations an incidental slip at one of the digits elicited a normal force increase at both engaged digits such that the normal:tangential force ratio was restored at the non-slipping digit and increased at the slipping digit. The initial development of the fingertip forces prior to object lift-off revealed that the subjects employed digit-specific anticipatory mechanisms using weight and frictional experiences in the previous trial. Because grasp stability was accomplished in a similar manner whether the task was carried out by one subject or cooperatively by two subjects, it was concluded that anticipatory adjustments of the fingertip forces can emerge from the action of anatomically independent neural networks controlling each engaged digit. In contrast, important aspects of the temporal coordination of the digits was organized by a “higher level” sensory – based control that influenced both digits. In lifts by single subjects this control was mast probably based on tactile and visual input and on communication between neural control mechanisms associated with each digit. In the two-subject grasp configuration this synchronization information was based on auditory and visual cues.

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole‐exome screening methods to detect disease‐causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole‐exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome‐tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD‐causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high‐throughput genomic approach enabled detection of disease‐related variants in unexpected genes; permitted detection of low‐grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

Genotype-phenotype correlations in Bothnia dystrophy caused by RLBP1 gene sequence variations

Purpose:  To evaluate phenotypes caused by different RLBP1 mutations in autosomal recessive retinitis pigmentosa of Bothnia type.

Genomic screening in rare disorders: New mutations and phenotypes, highlighting ALG14 as a novel cause of severe intellectual disability

We have investigated 20 consanguineous families with multiple children affected by rare disorders. Detailed clinical examinations, exome sequencing of affected as well as unaffected family members and further validation of likely pathogenic variants were performed. In 16/20 families, we identified pathogenic variants in autosomal recessive disease genes (ALMS1, PIGT, FLVCR2, TFG, CYP7B1, ALG14, EXOSC3, MEGF10, ASAH1, WDR62, ASPM, PNPO, ERCC5, KIAA1109, RIPK4, MAN1B1). A number of these genes have only rarely been reported previously and our findings thus confirm them as disease genes, further delineate the associated phenotypes and expand the mutation spectrum with reports of novel variants. We highlight the findings in two affected siblings with splice altering variants in ALG14 and propose a new clinical entity, which includes severe intellectual disability, epilepsy, behavioral problems and mild dysmorphic features, caused by biallelic variants in ALG14.