Does the model reflect the system? When two-dimensional biomechanics is not 'good enough'.

Models are mathematical representations of systems, processes or phenomena. In biomechanics, finite-element modelling (FEM) can be a powerful tool, allowing biologists to test form-function relationships in silico, replacing or extending results of in vivo experimentation. Although modelling simplifications and assumptions are necessary, as a minimum modelling requirement the results of the simplified model must reflect the biomechanics of the modelled system. In cases where the three-dimensional mechanics of a structure are important determinants of its performance, simplified two-dimensional modelling approaches are likely to produce inaccurate results. The vertebrate mandible is one among many three-dimensional anatomical structures routinely modelled using two-dimensional FE analysis. We thus compare the stress regimes of our published three-dimensional model of the chimpanzee mandible with a published two-dimensional model of the chimpanzee mandible and identify several fundamental differences. We then present a series of two-dimensional and three-dimensional FE modelling experiments that demonstrate how three key modelling parameters, (i) dimensionality, (ii) symmetric geometry, and (iii) constraints, affect deformation and strain regimes of the models. Our results confirm that, in the case of the primate mandible (at least), two-dimensional FEM fails to meet this minimum modelling requirement and should not be used to draw functional, ecological or evolutionary conclusions.

Mechanical compensation in the evolution of the early hominin feeding apparatus.

Australopiths, a group of hominins from the Plio-Pleistocene of Africa, are characterized by derived traits in their crania hypothesized to strengthen the facial skeleton against feeding loads and increase the efficiency of bite force production. The crania of robust australopiths are further thought to be stronger and more efficient than those of gracile australopiths. Results of prior mechanical analyses have been broadly consistent with this hypothesis, but here we show that the predictions of the hypothesis with respect to mechanical strength are not met: some gracile australopith crania are as strong as that of a robust australopith, and the strength of gracile australopith crania overlaps substantially with that of chimpanzee crania. We hypothesize that the evolution of cranial traits that increased the efficiency of bite force production in australopiths may have simultaneously weakened the face, leading to the compensatory evolution of additional traits that reinforced the facial skeleton. The evolution of facial form in early hominins can therefore be thought of as an interplay between the need to increase the efficiency of bite force production and the need to maintain the structural integrity of the face.

Neurobiology of ARID1B haploinsufficiency related to neurodevelopmental and psychiatric disorders.

ARID1B haploinsufficiency is a frequent cause of intellectual disability (ID) and autism spectrum disorder (ASD), and also leads to emotional disturbances. In this review, we examine past and present clinical and preclinical research into the neurobiological function of ARID1B. The presentation of ARID1B-related disorders (ARID1B-RD) is highly heterogeneous, including varying degrees of ID, ASD, and physical features. Recent research includes the development of suitable clinical readiness assessments for the treatment of ARID1B-RD, as well as similar neurodevelopmental disorders. Recently developed mouse models of Arid1b haploinsufficiency successfully mirror many of the behavioral phenotypes of ASD and ID. These animal models have helped to solidify the molecular mechanisms by which ARID1B regulates brain development and function, including epigenetic regulation of the Pvalb gene and promotion of Wnt/ß-catenin signaling in neural progenitors in the ventral telencephalon. Finally, preclinical studies have identified the use of a positive allosteric modulator of the GABAA receptor as an effective treatment for some Arid1b haploinsufficiency-related behavioral phenotypes, and there is potential for the refinement of this therapy in order to translate it into clinical use.

The cranial biomechanics and feeding performance of Homo floresiensis.

Homo floresiensis is a small-bodied hominin from Flores, Indonesia, that exhibits plesiomorphic dentognathic features, including large premolars and a robust mandible, aspects of which have been considered australopith-like. However, relative to australopith species, H. floresiensis exhibits reduced molar size and a cranium with diminutive midfacial dimensions similar to those of later Homo, suggesting a reduction in the frequency of forceful biting behaviours. Our study uses finite-element analysis to examine the feeding biomechanics of the H. floresiensis cranium. We simulate premolar (P3) and molar (M2) biting in a finite-element model (FEM) of the H. floresiensis holotype cranium (LB1) and compare the mechanical results with FEMs of chimpanzees, modern humans and a sample of australopiths (MH1, Sts 5, OH5). With few exceptions, strain magnitudes in LB1 resemble elevated levels observed in modern Homo. Our analysis of LB1 suggests that H. floresiensis could produce bite forces with high mechanical efficiency, but was subject to tensile jaw joint reaction forces during molar biting, which perhaps constrained maximum postcanine bite force production. The inferred feeding biomechanics of H. floresiensis closely resemble modern humans, suggesting that this pattern may have been present in the last common ancestor of Homo sapiens and H. floresiensis.

Comparative biomechanics of the Pan and Macaca mandibles during mastication: finite element modelling of loading, deformation and strain regimes.

The mechanical behaviour of the mandibles of Pan and Macaca during mastication was compared using finite element modelling. Muscle forces were calculated using species-specific measures of physiological cross-sectional area and scaled using electromyographic estimates of muscle recruitment in Macaca. Loading regimes were compared using moments acting on the mandible and strain regimes were qualitatively compared using maps of principal, shear and axial strains. The enlarged and more vertically oriented temporalis and superficial masseter muscles of Pan result in larger sagittal and transverse bending moments on both working and balancing sides, and larger anteroposterior twisting moments on the working side. The mandible of Pan experiences higher principal strain magnitudes in the ramus and mandibular prominence, higher transverse shear strains in the top of the symphyseal region and working-side corpus, and a predominance of sagittal bending-related strains in the balancing-side mandible. This study lays the foundation for a broader comparative study of Hominidae mandibular mechanics in extant and fossil hominids using finite element modelling. Pan's larger and more vertical masseter and temporalis may make it a more suitable model for hominid mandibular biomechanics than Macaca.

Drimolen cranium DNH 155 documents microevolution in an early hominin species.

Paranthropus robustus is a small-brained extinct hominin from South Africa characterized by derived, robust craniodental morphology. The most complete known skull of this species is DNH 7 from Drimolen Main Quarry, which differs from P. robustus specimens recovered elsewhere in ways attributed to sexual dimorphism. Here, we describe a new fossil specimen from Drimolen Main Quarry, dated from approximately 2.04-1.95 million years ago, that challenges this view. DNH 155 is a well-preserved adult male cranium that shares with DNH 7 a suite of primitive and derived features unlike those seen in adult P. robustus specimens from other chronologically younger deposits. This refutes existing hypotheses linking sexual dimorphism, ontogeny and social behaviour within this taxon, and clarifies hypotheses concerning hominin phylogeny. We document small-scale morphological changes in P. robustus associated with ecological change within a short time frame and restricted geography. This represents the most highly resolved evidence yet of microevolutionary change within an early hominin species.

Arid1b haploinsufficiency in parvalbumin- or somatostatin-expressing interneurons leads to distinct ASD-like and ID-like behavior.

Inhibitory interneurons are essential for proper brain development and function. Dysfunction of interneurons is implicated in several neurodevelopmental disorders, including autism spectrum disorder (ASD) and intellectual disability (ID). We have previously shown that Arid1b haploinsufficiency interferes with interneuron development and leads to social, cognitive, and emotional impairments consistent with ASD and ID. It is unclear, however, whether interneurons play a major role for the behavioral deficits in Arid1b haploinsufficiency. Furthermore, it is critical to determine which interneuron subtypes contribute to distinct behavioral phenotypes. In the present study, we generated Arid1b haploinsufficient mice in which a copy of the Arid1b gene is deleted in either parvalbumin (PV) or somatostatin (SST) interneurons, and examined their ASD- and ID-like behaviors. We found that Arid1b haploinsufficiency in PV or SST interneurons resulted in distinct features that do not overlap with one another. Arid1b haploinsufficiency in PV neurons contributed to social and emotional impairments, while the gene deletion in the SST population caused stereotypies as well as learning and memory dysfunction. These findings demonstrate a critical role of interneurons in Arid1b haploinsufficient pathology and suggest that PV and SST interneurons may have distinct roles in modulating neurological phenotypes in Arid1b haploinsufficiency-induced ASD and ID.

Nicotine Self-Administration With Tobacco Flavor Additives in Male Rats.

INTRODUCTION: Nicotine can robustly increase responding for conditioned reinforcers (CRs), stimuli that acquire reinforcing properties based on association with primary reinforcers. Menthol and licorice are tobacco flavoring agents also found in sweet foods (eg, candy and ice cream), making them putative CRs before they are consumed in tobacco. We sought to determine if intravenous self-administration (IVSA) of nicotine was enhanced by the inclusion of oral tobacco flavor CRs. METHODS: Menthol (160 or 320 µM) or licorice root extract (0.1% or 1%) were established as CRs (paired with 20% sucrose) or "neutral" stimuli (paired with water) in separate groups. During subsequent IVSA tests, nicotine was delivered in conjunction with oral presentations of the CR. RESULTS: In experiment 1, a menthol CR significantly shifted the peak nicotine dose from 15 µg/kg/infusion (Neutral group) to 3.25 µg/kg/infusion (CR group). In experiment 2, a menthol CR significantly increased operant licks for nicotine (3 µg/kg/infusion) relative to control groups. In experiment 3, both licorice and menthol CRs significantly increased operant licks for nicotine (7.5 µg/kg/infusion) relative to an "inactive" sipper. The licorice CR increased nicotine IVSA in proportion to the strength of the flavor, but both menthol concentrations increased nicotine IVSA to a similar extent. CONCLUSION: Tobacco flavor additives with conditioned reinforcing properties promote acquisition of nicotine self-administration at low unit doses and may have robust impact on tobacco consumption when nicotine yield is low. IMPLICATIONS: Tobacco flavor additives are found in rewarding foods (eg, ice cream) and gain palatability based on associations with primary rewards (eg, sugar) making them "conditioned reinforcers." Nicotine increases the motivation for flavor conditioned reinforcers and the present studies show that tobacco flavor additives can interact with nicotine to promote more nicotine self-administration. The interaction between flavors additives and nicotine may promote nicotine exposure and subsequently dependence.

The role of ARID1B, a BAF chromatin remodeling complex subunit, in neural development and behavior.

Haploinsufficiency of the chromatin remodeling factor ARID1B leads to autism spectrum disorder and intellectual disability. Several independent research groups, including our own, recently examined the effects of heterozygous deletion of Arid1b in mice and reported severe behavioral abnormalities reminiscent of autism spectrum disorders and intellectual disability as well as marked changes in gene expression and decreased body size. Arid1b heterozygous mice also display significant cortical excitatory/inhibitory imbalance due to altered GABAergic neuron numbers and impaired inhibitory synaptic transmission. Abnormal epigenetic modifications, including histone acetylation and methylation, are additionally associated with Arid1b haploinsufficiency in the brain. Treating adult Arid1b mutant mice with a positive GABA allosteric modulator, however, rescues multiple behavioral abnormalities, such as cognitive and social impairments, as well as elevated anxiety. While treating Arid1b haploinsufficient mice with recombinant mouse growth hormone successfully increases body size, it has no effect on aberrant behavior. Here we summarize the recent findings regarding the role of ARID1B in brain development and behavior and discuss the utility of the Arid1b heterozygous mouse model in neurodevelopmental and psychiatric research. We also discuss some of the opportunities and potential challenges in developing translational applications for humans and possible avenues for further research into the mechanisms of ARID1B pathology in the brain.

The role of MACF1 in nervous system development and maintenance.

Microtubule-actin crosslinking factor 1 (MACF1), also known as actin crosslinking factor 7 (ACF7), is essential for proper modulation of actin and microtubule cytoskeletal networks. Most MACF1 isoforms are expressed broadly in the body, but some are exclusively found in the nervous system. Consequentially, MACF1 is integrally involved in multiple neural processes during development and in adulthood, including neurite outgrowth and neuronal migration. Furthermore, MACF1 participates in several signaling pathways, including the Wnt/ß-catenin and GSK-3 signaling pathways, which regulate key cellular processes, such as proliferation and cell migration. Genetic mutation or dysregulation of the MACF1 gene has been associated with neurodevelopmental and neurodegenerative diseases, specifically schizophrenia and Parkinson's disease. MACF1 may also play a part in neuromuscular disorders and have a neuroprotective role in the optic nerve. In this review, the authors seek to synthesize recent findings relating to the roles of MACF1 within the nervous system and explore potential novel functions of MACF1 not yet examined.

MTOR controls genesis and autophagy of GABAergic interneurons during brain development.

Interneuron progenitors in the ganglionic eminence of the ventral telencephalon generate most cortical interneurons during brain development. However, the regulatory mechanism of interneuron progenitors remains poorly understood. Here, we show that MTOR (mechanistic target of rapamycin [serine/threonine kinase]) regulates proliferation and macroautophagy/autophagy of interneuron progenitors in the developing ventral telencephalon. To investigate the role of MTOR in interneuron progenitors, we conditionally deleted the Mtor gene in mouse interneuron progenitors and their progeny by using Tg(mI56i-cre,EGFP)1Kc/Dlx5/6-Cre-IRES-EGFP and Nkx2-1-Cre drivers. We found that Mtor deletion markedly reduced the number of interneurons in the cerebral cortex. However, relative positioning of cortical interneurons was normal, suggesting that disruption of progenitor self-renewal caused the decreased number of cortical interneurons in the Mtor-deleted brain. Indeed, Mtor-deleted interneuron progenitors showed abnormal proliferation and cell cycle progression. Additionally, we detected a significant activation of autophagy in Mtor-deleted brain. Our findings suggest that MTOR plays a critical role in the regulation of cortical interneuron number and autophagy in the developing brain.

The Biomechanics of Bony Facial "Buttresses" in South African Australopiths: An Experimental Study Using Finite Element Analysis.

Australopiths exhibit a number of derived facial features that are thought to strengthen the face against high and/or repetitive loads associated with a diet that included mechanically challenging foods. Here, we use finite element analysis (FEA) to test hypotheses related to the purported strengthening role of the zygomatic root and "anterior pillar" in australopiths. We modified our previously constructed models of Sts 5 (Australopithecus africanus) and MH1 (A. sediba) to differ in the morphology of the zygomatic root, including changes to both the shape and positioning of the zygomatic root complex, in addition to creating variants of Sts 5 lacking anterior pillars. We found that both an expanded zygomatic root and the presence of "anterior pillars" reinforce the face against feeding loads. We also found that strain orientations are most compatible with the hypothesis that the pillar evolved to resist loads associated with premolar loading, and that this morphology has an ancillary effect of strengthening the face during all loading regimes. These results provide support for the functional hypotheses. However, we found that an anteriorly positioned zygomatic root increases strain magnitudes even in models with an inflated/reinforced root complex. These results suggest that an anteriorly placed zygomatic root complex evolved to enhance the efficiency of bite force production while facial reinforcement features, such as the anterior pillar and the expanded zygomatic root, may have been selected for in part to compensate for the weakening effect of this facial configuration. Anat Rec, 300:171-195, 2017. © 2016 Wiley Periodicals, Inc.

The Biomechanics of Zygomatic Arch Shape.

Mammalian zygomatic arch shape is remarkably variable, ranging from nearly cylindrical to blade-like in cross section. Based on geometry, the arch can be hypothesized to be a sub-structural beam whose ability to resist deformation is related to cross sectional shape. We expect zygomatic arches with different cross sectional shapes to vary in the degree to which they resist local bending and torsion due to the contraction of the masseter muscle. A stiffer arch may lead to an increase in the relative proportion of applied muscle load being transmitted through the arch to other cranial regions, resulting in elevated cranial stress (and thus, strain). Here, we examine the mechanics of the zygomatic arch using a series of finite element modeling experiments in which the cross section of the arch of Pan troglodytes has been modified to conform to idealized shapes (cylindrical, elliptical, blade-like). We find that the shape of the zygomatic arch has local effects on stain that do not conform to beam theory. One exception is that possessing a blade-like arch leads to elevated strains at the postorbital zygomatic junction and just below the orbits. Furthermore, although modeling the arch as solid cortical bone did not have the effect of elevating strains in other parts of the face, as had been expected, it does have a small effect on stress associated with masseter contraction. These results are counterintuitive. Even though the arch has simple beam-like geometry, we fail to find a simple mechanical explanation for the diversity of arch shape. Anat Rec, 299:1734-1752, 2016. © 2016 Wiley Periodicals, Inc.

Internal Bone Architecture in the Zygoma of Human and Pan.

The internal and external anatomy of the primate zygoma is central to orofacial function, health, and disease. The importance of variation in its gross morphology across extinct and extant primate forms has been established using finite element analysis, but its internal structure has yet to be explored. In this study, µCT is used to characterize trabecular bone morphometry in two separate regions of the zygoma of humans and Pan. Trabecular anisotropy and orientation are compared with strain orientations observed in trabecular regions of finite element models of four Pan crania. The results of this study show that trabecular bone morphometry, anisotropy, and orientation are highly compatible with strain orientation and magnitude in the finite element models. Trabecular bone in the zygoma is largely orthotropic (with bone orientation differing in three mutually orthogonal directions), with its primary orientation lying in the mediolateral direction. Trabecular bone in the zygomatic region appears to be highly influenced by the local strain environment, and thus may be closely linked to orofacial function. Anat Rec, 299:1704-1717, 2016. © 2016 Wiley Periodicals, Inc.

Review of In Vivo Bone Strain Studies and Finite Element Models of the Zygomatic Complex in Humans and Nonhuman Primates: Implications for Clinical Research and Practice.

The craniofacial skeleton is often described in the clinical literature as being comprised of vertical bony pillars, which transmit forces from the toothrow to the neurocranium as axial compressive stresses, reinforced transversely by buttresses. Here, we review the literature on bony microarchitecture, in vivo bone strain, and finite-element modeling of the facial skeleton of humans and nonhuman primates to address questions regarding the structural and functional existence of facial pillars and buttresses. Available bone material properties data do not support the existence of pillars and buttresses in humans or Sapajus apella. Deformation regimes in the zygomatic complex emphasize bending and shear, therefore conceptualizing the zygomatic complex of humans or nonhuman primates as a pillar obscures its patterns of stress, strain, and deformation. Human fossil relatives and chimpanzees exhibit strain regimes corroborating the existence of a canine-frontal pillar, but the notion of a zygomatic pillar has no support. The emerging consensus on patterns of strain and deformation in finite element models (FEMs) of the human facial skeleton corroborates hypotheses in the clinical literature regarding zygomatic complex function, and provide new insights into patterns of failure of titanium and resorbable plates in experimental studies. It is suggested that the "pillar and buttress" model of human craniofacial skeleton function be replaced with FEMs that more accurately and precisely represent in vivo function, and which can serve as the basis for future research into implants used in restoration of occlusal function and fracture repair. Anat Rec, 299:1753-1778, 2016. © 2016 Wiley Periodicals, Inc.

Human feeding biomechanics: performance, variation, and functional constraints.

The evolution of the modern human (Homo sapiens) cranium is characterized by a reduction in the size of the feeding system, including reductions in the size of the facial skeleton, postcanine teeth, and the muscles involved in biting and chewing. The conventional view hypothesizes that gracilization of the human feeding system is related to a shift toward eating foods that were less mechanically challenging to consume and/or foods that were processed using tools before being ingested. This hypothesis predicts that human feeding systems should not be well-configured to produce forceful bites and that the cranium should be structurally weak. An alternate hypothesis, based on the observation that humans have mechanically efficient jaw adductors, states that the modern human face is adapted to generate and withstand high biting forces. We used finite element analysis (FEA) to test two opposing mechanical hypotheses: that compared to our closest living relative, chimpanzees (Pan troglodytes), the modern human craniofacial skeleton is (1) less well configured, or (2) better configured to generate and withstand high magnitude bite forces. We considered intraspecific variation in our examination of human feeding biomechanics by examining a sample of geographically diverse crania that differed notably in shape. We found that our biomechanical models of human crania had broadly similar mechanical behavior despite their shape variation and were, on average, less structurally stiff than the crania of chimpanzees during unilateral biting when loaded with physiologically-scaled muscle loads. Our results also show that modern humans are efficient producers of bite force, consistent with previous analyses. However, highly tensile reaction forces were generated at the working (biting) side jaw joint during unilateral molar bites in which the chewing muscles were recruited with bilateral symmetry. In life, such a configuration would have increased the risk of joint dislocation and constrained the maximum recruitment levels of the masticatory muscles on the balancing (non-biting) side of the head. Our results do not necessarily conflict with the hypothesis that anterior tooth (incisors, canines, premolars) biting could have been selectively important in humans, although the reduced size of the premolars in humans has been shown to increase the risk of tooth crown fracture. We interpret our results to suggest that human craniofacial evolution was probably not driven by selection for high magnitude unilateral biting, and that increased masticatory muscle efficiency in humans is likely to be a secondary byproduct of selection for some function unrelated to forceful biting behaviors. These results are consistent with the hypothesis that a shift to softer foods and/or the innovation of pre-oral food processing techniques relaxed selective pressures maintaining craniofacial features that favor forceful biting and chewing behaviors, leading to the characteristically small and gracile faces of modern humans.

Effects of Sex and Mild Intrainsult Hypothermia on Neuropathology and Neural Reorganization following Neonatal Hypoxic Ischemic Brain Injury in Rats.

Hypoxia ischemia (HI) is a recognized risk factor among late-preterm infants, with HI events leading to varied neuropathology and cognitive/behavioral deficits. Studies suggest a sex difference in the incidence of HI and in the severity of subsequent behavioral deficits (with better outcomes in females). Mechanisms of a female advantage remain unknown but could involve sex-specific patterns of compensation to injury. Neuroprotective hypothermia is also used to ameliorate HI damage and attenuate behavioral deficits. Though currently prescribed only for HI in term infants, cooling has potential intrainsult applications to high-risk late-preterm infants as well. To address this important clinical issue, we conducted a study using male and female rats with a postnatal (P) day 7 HI injury induced under normothermic and hypothermic conditions. The current study reports patterns of neuropathology evident in postmortem tissue. Results showed a potent benefit of intrainsult hypothermia that was comparable for both sexes. Findings also show surprisingly different patterns of compensation in the contralateral hemisphere, with increases in hippocampal thickness in HI females contrasting reduced thickness in HI males. Findings provide a framework for future research to compare and contrast mechanisms of neuroprotection and postinjury plasticity in both sexes following a late-preterm HI insult.

Mechanical evidence that Australopithecus sediba was limited in its ability to eat hard foods.

Australopithecus sediba has been hypothesized to be a close relative of the genus Homo. Here we show that MH1, the type specimen of A. sediba, was not optimized to produce high molar bite force and appears to have been limited in its ability to consume foods that were mechanically challenging to eat. Dental microwear data have previously been interpreted as indicating that A. sediba consumed hard foods, so our findings illustrate that mechanical data are essential if one aims to reconstruct a relatively complete picture of feeding adaptations in extinct hominins. An implication of our study is that the key to understanding the origin of Homo lies in understanding how environmental changes disrupted gracile australopith niches. Resulting selection pressures led to changes in diet and dietary adaption that set the stage for the emergence of our genus.

Sex differences in behavioral outcomes following temperature modulation during induced neonatal hypoxic ischemic injury in rats.

Neonatal hypoxia ischemia (HI; reduced oxygen and/or blood flow to the brain) can cause various degrees of tissue damage, as well as subsequent cognitive/behavioral deficits such as motor, learning/memory, and auditory impairments. These outcomes frequently result from cardiovascular and/or respiratory events observed in premature infants. Data suggests that there is a sex difference in HI outcome, with males being more adversely affected relative to comparably injured females. Brain/body temperature may play a role in modulating the severity of an HI insult, with hypothermia during an insult yielding more favorable anatomical and behavioral outcomes. The current study utilized a postnatal day (P) 7 rodent model of HI injury to assess the effect of temperature modulation during injury in each sex. We hypothesized that female P7 rats would benefit more from lowered body temperatures as compared to male P7 rats. We assessed all subjects on rota-rod, auditory discrimination, and spatial/non-spatial maze tasks. Our results revealed a significant benefit of temperature reduction in HI females as measured by most of the employed behavioral tasks. However, HI males benefitted from temperature reduction as measured on auditory and non-spatial tasks. Our data suggest that temperature reduction protects both sexes from the deleterious effects of HI injury, but task and sex specific patterns of relative efficacy are seen.