Several neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia (SCA) are caused by non‐coding nucleotide repeat expansions. Different pathogenic mechanisms may underlie these non‐coding repeat expansion disorders. While gain‐of‐function mechanisms, such as toxicity associated with expression of repeat RNA or toxicity associated with repeat‐associated non‐ATG (RAN) products, are most frequently connected with these disorders, loss‐of‐function mechanisms have also been implicated. We review the different pathways that have been linked to non‐coding repeat expansion disorders such as C9ORF72‐linked ALS/frontotemporal dementia (FTD), myotonic dystrophy, fragile X tremor/ataxia syndrome (FXTAS), SCA, and Huntington's disease‐like 2. We discuss modes of RNA toxicity focusing on the identity and the interacting partners of the toxic RNA species. Using the C9ORF72 ALS/FTD paradigm, we further explore the efforts and different methods used to disentangle RNA vs. RAN toxicity. Overall, we conclude that there is ample evidence for a role of RNA toxicity in non‐coding repeat expansion diseases.

The exact mechanism underlying amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) associated with the GGGGCC repeat expansion in C9orf72 is still unclear. Two gain-of-function mechanisms are possible: repeat RNA toxicity and dipeptide repeat protein (DPR) toxicity. We here dissected both possibilities using a zebrafish model for ALS. Expression of two DPRs, glycine–arginine and proline–arginine, induced a motor axonopathy. Similarly, expanded sense and antisense repeat RNA also induced a motor axonopathy and formed mainly cytoplasmic RNA foci. However, DPRs were not detected in these conditions. Moreover, stop codon-interrupted repeat RNA still induced a motor axonopathy and a synergistic role of low levels of DPRs was excluded. Altogether, these results show that repeat RNA toxicity is independent of DPR formation. This RNA toxicity, but not the DPR toxicity, was attenuated by the RNA-binding protein Pur-alpha and the autophagy-related protein p62. Our findings demonstrate that RNA toxicity, independent of DPR toxicity, can contribute to the pathogenesis of C9orf72-associated ALS/FTD.

Subcortical structures are a relative neurophysiological 'terra incognita' owing to their location within the skull. While perioperative subcortical sensing has been performed for more than 20 years, the neurophysiology of the basal ganglia in the home setting has remained almost unexplored. However, with the recent advent of implantable pulse generators (IPG) that are able to record neural activity, the opportunity to chronically record local field potentials (LFPs) directly from electrodes implanted for deep brain stimulation opens up. This allows for a breakthrough of chronic subcortical sensing into fundamental research and clinical practice. In this review an extensive overview of the current state of subcortical sensing is provided. The widespread potential of chronic subcortical sensing for investigational and clinical use is discussed. Finally, status and future perspectives of the most promising application of chronic subcortical sensing -i.e., adaptive deep brain stimulation (aDBS)- are discussed in the context of movement disorders. The development of aDBS based on both chronic subcortical and cortical sensing has the potential to dramatically change clinical practice and the life of patients with movement disorders. However, several barriers still stand in the way of clinical implementation. Advancements regarding IPG and lead technology, physiomarkers, and aDBS algorithms as well as harnessing artificial intelligence, multimodality and sensing in the naturalistic setting are needed to bring aDBS to clinical practice.

Objective. Local field potential (LFP) recordings using chronically implanted sensing-enabled stimulators are a powerful tool for indexing symptom presence and severity in neurological and neuropsychiatric disorders, and for enhancing our neurophysiological understanding of brain processes. LFPs have gained interest as input signals for closed-loop deep brain stimulation (DBS) and can be used to inform DBS parameter selection. LFP recordings using chronically implanted sensing-enabled stimulators have various implementational challenges. Approach. Here we describe our collective experience using BrainSense (Medtronic®) for clinical and research work. We aim to provide insightful tips and practical advice to empower readers with the knowledge needed to navigate the intricacies of the device and make the most out of its features. Main results. The central issues that apply to several BrainSense features encompass restricted compatibility of stimulation configuration with sensing, differences in electrophysiological signal properties between ‘stimulation OFF’ and ‘stimulation ON at 0.0 mA’, and challenges associated with the internal clock of the neurostimulator. In addition, since recordings are obtained from bipolar and not monopolar channels, spatial certainty regarding the distribution of LFPs around the DBS electrode is limited. Several options exist to synchronize LFP time series with external data streams, but standardization and generalization are lacking. The use of at-home chronic LFP recording is limited by a low temporal and spectral resolution. Regarding at-home LFP snapshots, LFP time series are not stored, parts of the power spectrum are censored when stimulating at high or low frequencies, and the stimulation amplitude is not readily available. Significance. We discussed practical applications, implementation, system limitations, and pitfalls with the aim that sensing can be better applied for clinical practice and research.

The residual stresses generated during different processing steps and during thermal cycling of 3D stack packages, mimicking its service life, are quantified by Finite Element Modeling (FEM) together with measurements of dedicated FET arrays used as CPI sensors. Thermo-mechanical deformation of the package can be directly transferred to the Cu/low-k interconnect, inducing large local stresses to drive interfacial crack formation and propagation. The test vehicle used in this work is an imec's proprietary logic CMOS IC on top of which a commercial DRAM is stacked. Different test structures contained in the chip, allow monitoring thermo-mechanical stresses and electrical characteristics of TSV's and micro-bumps. It is shown that FET current shifts can be used to measure the stress in the surface of the chip. The use of standard FEM approach is insufficient to simulate the CPI due to the large dimensional difference between the packaging and interconnects structures. Due to size and speed limitations of commercial computers, a 3D thermo mechanical model of a 3D package cannot contain all the details from the package and at the same time simulate the small structures such as metal and dielectric layers in the BEOL. For this reason, multi-scale simulations are the best choice for identifying the critical regions of the package where high stresses and/or delamination failures are expected to occur. We have shown the methodology to follow to study the CPI.

The influence of thinning standard 130-nm CMOS technology device wafers to residual silicon thicknesses of 20 and 5 mum has been studied. Electrical performance was evaluated at wafer level by characterizing various basic device parameters before and after thinning. An increase in the well sheet resistance and a reduction in the gate leakage current were observed. However, both at 25degC and 100degC, no performance degradation was found that could be correlated to the applied thinning techniques, including extreme grinding down to 5 mum. These electrical results are consistent with the experimentally observed submicrometer thinning-induced subsurface damage. Hence, the feasibility of extreme thinning in 3-D integration schemes for standard bulk-Si CMOS was demonstrated.