Probing Mechanical Properties of Brain in a Tuberous Sclerosis Model of Autism

Abstract

Causes of autism spectrum disorders (ASD) are understood poorly, making diagnosis and treatment challenging. While many studies have investigated the biochemical and genetic aspects of ASD, whether and how mechanical characteristics of the autistic brain can modulate neuronal connectivity and cognition in ASD are unknown. Previously, it has been shown that ASD brains are characterized by abnormal white matter and disorganized neuronal connectivity; we hypothesized that these significant cellular-level structural changes may translate to changes in the mechanical properties of the autistic brain or regions therein. Here, we focused on tuberous sclerosis complex (TSC), a genetic disorder with a high penetrance of ASD. We investigated mechanical differences between murine brains obtained from control and TSC cohorts at various deformation length- and time-scales. At the microscale, we conducted creep-compliance and stress relaxation experiments using atomic force microscope(AFM)-enabled indentation. At the mesoscale, we conducted impact indentation using a pendulum-based instrumented indenter to extract mechanical energy dissipation metrics. At the macroscale, we used oscillatory shear rheology to quantify the frequency-dependent shear moduli. Despite significant changes in the cellular organization of TSC brain tissue, we found no corresponding changes in the quantified mechanical properties at every length- and time-scale explored. This investigation of the mechanical characteristics of the brain has broadened our understanding of causes and markers of TSC/ASD, while raising questions about whether any mechanical differences can be detected in other animal models of ASD or other disease models that also feature abnormal brain structure.

Acute but not inherited demyelination in mouse models leads to brain tissue stiffness changes

“…S2 B, B'), which did not result in changed tissue stiffness, raising the question whether the observed structural tissue changes have a significant influence on tissue stiffness. Notably, similar brain stiffness analysis in a mouse model of tuberous sclerosis complex (TSC), which is another inherited neurological disease characterized by structurally altered brain tissue and hypomyelination, did not show stiffness difference between TSC and wild-type tissue 51 , similar to shiverer mice. Third, microglia and astrocytes proliferate and migrate to the lesion site to clean up cell debris 52 in response to cuprizone-induced demyelination.…”

Photoacoustic viscoelasticity assessment of prefrontal cortex and cerebellum in normal and prenatal valproic acid-exposed rats

“…Currently, some ASD-related quantitative differences in brain morphometry in various regions (particularly in the prefrontal cortex and cerebellum) have been rendered [5] . Abnormalities in white matter and disorganized neuronal connectivity have also been previously shown in ASD brains [7] . However, whether any mechanical changes can be detected in the brain areas and regions in an autistic-like model (such as maternal exposure of rats to VPA) has not been reported yet.…”

“…In the other respect, previous studies demonstrated that white matter stiffness and myelin content exhibit a strong correlation [7] , and the brain water level changes during the myelination process. As the brain matures, increasing myelination shows a concomitance decrease in brain water content, also shown in the cerebellum [69] , [70] .…”

“…Furthermore, it is generally agreed that the brain tissue’s mechanical properties not only strongly influence normal brain function and development but also can alter the progression of neurological disorders [5] . Several studies have shown a direct correlation between abnormal mechanical properties and neurodegenerative conditions, such as Alzheimer’s disease, encephalomyelitis, and multiple sclerosis [7] . Currently, some ASD-related quantitative differences in brain morphometry in various regions (particularly in the prefrontal cortex and cerebellum) have been rendered [5] .…”

“…Examining the local mechanical properties of the brain tissue in pathological conditions would enable scientists to shed light on the new area of exploration for treatment targets or diagnostic markers in ASD that may affect brain structure. Moreover, the brain is mechanically more compliant than other biological tissues and can exhibit viscoelastic deformations [7] . A quantitative evaluation of the viscoelasticity characteristics of the multiple brain areas might pave an appealing new way for finding the underlying mechanisms contributing to the functioning of the normal brain and neurodevelopmental disorders.…”