Research has shown that the surrounding biomechanical environment plays a significant role in the development, differentiation, repair, and degradation of tendon, but the interactions between tendon cells and the forces they experience are complex. In vitro mechanical stimulation models attempt to understand the effects of mechanical load on tendon and connective tissue progenitor cells. This article reviews multiple mechanical stimulation models used to study tendon mechanobiology and provides an overview of the current progress in modelling the complex native biomechanical environment of tendon. Though great strides have been made in advancing the understanding of the role of mechanical stimulation in tendon development, damage, and repair, there exists no ideal in vitro model. Further comparative studies and careful consideration of loading parameters, cell populations, and biochemical additives may further offer new insight into an ideal model for the support of tendon regeneration studies.

Background/aims

Thalamic deep brain stimulation (DBS) for the treatment of medically refractory pain has largely been abandoned on account of its inconsistent and oftentimes poor efficacy. Our aim here was to use diffusion tensor imaging (DTI)-based segmentation to assess the internal thalamic nuclei of patients who have undergone thalamic DBS for intractable pain and retrospectively correlate lead position with clinical outcome.

Methods

DTI-based segmentation was performed on 5 patients who underwent sensory thalamus DBS for chronic pain. Postoperative computed tomography images obtained for electrode placement were fused with preoperative magnetic resonance images that had undergone DTI-based thalamic segmentation. Sensory thalamus maps of 4 patients were analyzed for lead positioning and interpatient variability.

Results

Four patients who experienced significant pain relief following DBS demonstrated contact positions within the DTI-determined sensory thalamus or in its vicinity, whereas 1 patient who did not respond to stimulation did not. Only 4 voxels (2%) within the sensory thalamus were mutually shared among patients; 108 voxels (58%) were uniquely represented.

Conclusions

DTI-based segmentation of the thalamus can be used to confirm thalamic lead placement relative to the sensory thalamus and may serve as a useful tool to guide thalamic DBS electrode implantation in the future.

Introduction: Ventriculoperitoneal (VP) shunts divert cerebrospinal fluid (CSF) out of cerebral ventricles in patients with hydrocephalus or elevated intracranial pressure (ICP). Despite high failure rates, there exist limited clinically viable solutions for long-term and continuous outpatient monitoring of CSF flow rate through VP shunts. We present a novel, low-power method for sensing analog CSF flow rate through a VP shunt premised on induced spatial electrical charge variation. Methods: Two geometric variants of the proposed sensing mechanism were prototyped: linear wire (P1) and cylindrical (P2) electrodes. Normal saline was gravity-driven through P1 and a commercially available shunt system in series. True flow rates were measured using a high-precision analytical balance. Subsequently, artificial CSF was driven by a programmable syringe pump through P2. Flow rate prediction models were empirically derived and tested. Sensor response was also assessed during simulated obstruction trials. Finally, power consumption per flow measurement was measured. Results: P1 (17 mm long) and P2 (22 mm long) averaged 7.2% and 4.2% error, respectively, in flow rate measurement from 0.01 to 0.90 mL/min. Response curves exhibited an appreciably flattened profile during obstruction trials compared to non-obstructed states. P2 consumed 37.5 µJoules per flow measurement. Conclusion: We propose a novel method for accurately sensing CSF flow rate through a VP shunt and validate this method at the benchtop with normal saline and artificial CSF over a board range of flows (0.01-0.90 mL/min). The sensing element is highly power efficient, compact, insertable into existing shunt and valve assemblies, and does not alter CSF flow mechanics.

Abstract Silent pituitary corticotroph tumors derive from the Tpit (aka TBX19) pituitary lineage. Accounting for ~ 30% of corticotroph tumors, they are not infrequently clinically aggressive and invade locally into adjacent sellar structures, making complete surgical resection challenging and contributing to their higher recurrence rates. How silent and active corticotroph tumor subtypes differ is not clear although some studies reported that silent corticotroph tumors exhibit reduced PC1 expression causing impaired POMC processing. We used single cell RNAseq to compare the transcriptome between silent (n = 2) and active (n = 4) corticotroph tumors at the single cell level. We obtained an average of 265 million reads, and 24,682 genes per patient with an average of 1,240 genes expressed and 3,5442 unique molecular identifiers (UMIs) detected per cell. We further defined 5 distinct cell populations from a total of 23,269 cells, namely tumor cells (62%), stromal cells (25%), immune cells (7%), progenitor cells (5%), and a minor population of erythrocytes (1%). Tumor cells clustered in an origin-dependent manner and all expressed POMC and TBX19. However, the gene signatures of silent and active corticotroph tumors differed in 3 major aspects. Firstly, and supporting prior studies, a series of hormone processing peptidase genes, including PC1 (aka PCSK1), PDIA3, SEC11C, SPCS1 and CTSB, were reduced in silent corticotroph tumors (p=5.54e-5) compared to active corticotroph tumors. Secondly, genes involved in organization of secretory vesicles such as SCG5, TIMP1, VGF, SYT17, LGALS3 and CALY were also reduced in silent corticotroph tumors, which could further compound their inability to secrete ACTH. Thirdly, the silent corticotroph tumors exhibited several features of endothelial-to-mesenchymal transition (EMT), including increased expression of the mesenchymal genes CDH2 (aka NCAD), COL1A1, PCDH9, FGF5, ID2 (p=8.4e-3), and loss of EPCAM, which regulate cell migration and movement. Upstream analysis suggested that aberrant STAT3 activation may be related to these changes. Consequently, we noted that the stromal content was higher in silent corticotroph tumors (47.5% vs. 18.13%), concordant with the observed EMT de-differentiation of tumor cells. In summary, our scRNAseq analysis provides an unprecedented precise investigation of the transcriptomic features of thousands of heterogenous corticotroph tumor cells simultaneously. We demonstrate that although silent corticotroph tumor cells still express the pituitary lineage markers PITX1 and TBX19, they exhibit EMT, potentially affording increased migratory capacity at the cost of reduced neuroendocrine function with inability to produce and secrete mature ACTH. Our findings provide novel insights into the pathogenesis of silent versus active corticotroph tumor, but may reveal novel molecular targets for treatment of these challenging tumors.

Background

Several centers have reported efficacious cluster headache suppression with deep brain stimulation (DBS) of the hypothalamic region using a variety of targets. While the connectivity of some of these targets has individually been studied, commonalities across these targets, especially with respect to network-level connectivity, have not previously been explored.

Methods

We examined the anatomic connectivity of the four distinct DBS targets reported in the literature using probabilistic diffusion tensor tractography in normal subjects.

Results

Despite being described as hypothalamic, the DBS targets localized in the midbrain tegmentum posterior to the hypothalamus. Common tracts across DBS targets and subjects included projections to the ipsilateral hypothalamus, reticular formation, and cerebellum.

Discussion

Although DBS target coordinates are not located within the hypothalamus, a strong connection between DBS targets and the hypothalamus likely exists. Moreover, a common projection to the medial ipsilateral cerebellum was identified. Understanding the common connectivity of DBS-targeted regions may elucidate anatomic pathways that are involved in modulating cluster headache attacks and facilitate more precise patient-specific targeting of DBS.

Essential tremor and Parkinson's disease-associated tremor are extremely prevalent within the field of movement disorders. The ventral intermediate (VIM) nucleus of the thalamus has been commonly used as both a neuromodulatory and neuroablative target for the treatment of these forms of tremor. With both deep brain stimulation and Gamma Knife radiosurgery, there is an abundance of literature regarding the surgical planning, targeting, and outcomes of these methodologies. To date, there have been no reports of frameless, linear accelerator (LINAC)-based thalomotomies for tremor. The authors report the case of a patient with tremor-dominant Parkinson's disease, with poor tremor improvement with medication, who was offered LINAC-based thalamotomy. High-resolution 0.9-mm isotropic MR images were obtained, and simulation was performed via CT with 1.5-mm contiguous slices. The VIM thalamic nucleus was determined using diffusion tensor imaging (DTI)-based segmentation on FSL using probabilistic tractography. The supplemental motor and premotor areas were the cortical target masks. The authors centered their isocenter within the region of the DTI-determined target and treated the patient with 140 Gy in a single fraction. The DTI-determined target had coordinates of 14.2 mm lateral and 8.36 mm anterior to the posterior commissure (PC), and 3 mm superior to the anterior commissure (AC)-PC line, which differed by 3.30 mm from the original target determined by anatomical considerations (15.5 mm lateral and 7 mm anterior to the PC, and 0 mm superior to the AC-PC line). There was faint radiographic evidence of lesioning at the 3-month follow-up within the target zone, which continued to consolidate on subsequent scans. The patient experienced continued right upper-extremity resting tremor improvement starting at 10 months until it was completely resolved at 22 months of follow-up. Frameless LINAC-based thalamotomy guided by DTI-based thalamic segmentation is a feasible method for achieving radiosurgical lesions of the VIM thalamus to treat tremor.

LITT is a minimally-invasive laser ablation technique used to treat a wide variety of intracranial lesions. Difficulties performing intraoperative mapping have limited its adoption for lesions in/near eloquent regions. In this institutional case series, we demonstrate the utility of fMRI-adjunct planning for LITT near language or motor areas. Six out of 7 patients proceeded with LITT after fMRI-based tractography determined adequate safety margins for ablation. All underwent successful ablation without new or worsening postoperative symptoms requiring adjuvant corticosteroids, including those with preexisting deficits. fMRI is an easily accessible adjunct which may potentially reduce chances of complications in LITT near eloquent structures.

PURPOSE: To investigate the pathological change of the glymphatic system in idiopathic normal pressure hydrocephalus (iNPH) using diffusion tensor imaging (DTI) analysis. MATERIALS AND METHODS: 24 right-handed patients were referred to our hydrocephalus clinic for assessment of ventriculomegaly and gait impairment. 12 of 24 were diagnosed as pseudo-iNPH (piNPH) based on assessment by a neurologist. Diffusivity maps in the direction of the x-axis (right-to-left) (Dx), y-axis (anterior-to-posterior) (Dy), and z-axis (inferior-to-superior) (Dz) were computed. The diffusion map was coregistered to International Consortium for Brain Mapping (ICBM) DTI-81 atlas. The analysis along the perivascular space (ALPS) index was defined as mean (Dxpro, Dypro)/mean (Dypro, Dzasc), where Dxpro and Dxasc are Dx values in the projection and association fiber areas, respectively. Evans index and callosal angle were also assessed on each case. RESULTS: ALPS indexes of the control, piNPH, and iNPH cases were 1.18 ± 0.08, 1.08 ± 0.03, and 0.94 ± 0.06, respectively, and there were significant differences among the groups (control vs. piNPH, P = 0.003; control vs. iNPH P < 0.001; piNPH vs. iNPH, P < 0.001). Area under curve (AUC) was 0.92, 1.00, and 1.00 on control vs. piNPH, control vs. iNPH, and piNPH vs. iNPH on ROC analysis. Between piNPH and NPH, ALPS index has higher diagnostic performance than Evans index and callosal angle (AUC = 1.00 vs. 0.84, P = 0.028; AUC = 1.00 vs. 0.74, P = 0.016). CONCLUSION: Atlas-based ALPS index using the DTI method differentiated among iNPH, piNPH, and controls clearly.

Purpose

Stereotactic radiosurgery (SRS) provides a noninvasive treatment modality for patients with medically refractory trigeminal neuralgia. The root entry zone (REZ) has been proposed to be an ideal stereotactic target because it is partially composed of centrally produced myelin, conferring a theoretical increased sensitivity to irradiation as well as increased susceptibility to neurovascular conflict, making it the site in which nociceptive signals likely arise. The aim of this study is to determine if there is a statistically and clinically significant difference in pain relief or facial hypesthesia following SRS based on distance of the stereotactic isocenter from REZ.

Methods and materials

Patients undergoing Novalis radiosurgery for the treatment of trigeminal neuralgia with at least 3 months' follow-up were included in this study. Postoperative outcomes were stratified by Barrow Neurological Institute (BNI) score for pain relief and BNI facial numbness score for facial hypesthesia.

Results

Sixty-seven patients met inclusion criteria and were included in this study. BNI score of I-IIIa was attained in 82% of patients at 3 months and 65% at 1 year following SRS. Distance from isocenter to REZ varied from 0 to 8.6 mm, with a mean of 1.94 ± 1.62 mm. Logistic regression of target-REZ distance against pain relief outcome (patients with score I-IIIa and IIIb-V) was insignificant at 3 months (P = .988), 6 months (P = .925), 9 months (P = .845), and 12 months (P = .547) postoperatively. Furthermore, no significant correlation was found with logistic regression of target-REZ distance with pain relief outcome (patients with score I and score II-IV) (P = .544).

Conclusions

The current analysis suggests that distance from REZ does not correlate with degree of postoperative pain relief or facial hypesthesia; thus, targeting specific regions within the trigeminal nerve in relation to these anatomical characteristics may not afford any advantage from this perspective.

The spectrum of cognitive symptoms in Parkinson's disease (PD) can span various domains, including executive function, language, attention, memory, and visuospatial skills. These symptoms may be attributable to the degradation of projection fibers associated with the underlying neurodegenerative process. The primary purpose of this study is to find microstructural correlates of impairments across these cognitive domains in PD using diffusion tensor imaging (DTI). Sixteen patients with PD with comprehensive neuropsychological evaluation and DTI data were retrospectively studied. Fractional anisotropy (FA) and mean diffusivity (MD) were assessed using regions-of-interest (ROI) analysis and confirmed with a voxel-based approach. Executive function directly correlated with FA and inversely correlated with MD in mostly frontal white matter tracts, especially the anterior limb of the internal capsule and genu of the corpus callosum. Likewise, language and attentional performance demonstrated correlations with DTI parameters in the frontal regions, but the attention domain additionally recruited regions widespread throughout the brain, with the most significant correlation identified in cingulate gyrus (cingulum). Lastly, memory impairment mainly involved MD alterations within the fornix. No significant correlations were found between visuospatial skills and DTI measures. Despite some overlap, unique patterns of white matter diffusivity underlie impairments in distinct cognitive domains in patients with PD. DTI combined with neurocognitive tests may be a valuable biomarker for identifying cognitive impairments in PD.