Background Deep Brain Stimulation (DBS) is thought to improve the symptoms of selected neurological disorders by modulating activity within dysfunctional brain circuits. To date, there is no evidence that DBS counteracts progressive neurodegeneration in any particular disorder. Objective/Hypothesis We hypothesized that DBS applied to the fornix in patients with Alzheimer’s Disease (AD) could have an effect on brain structure. Methods In six AD patients receiving fornix DBS, we used structural MRI to assess one-year change in hippocampal, fornix, and mammillary body volume. We also used deformation-based morphometry to identify whole-brain structural changes. We correlated volumetric changes to hippocampal glucose metabolism. We also compared volumetric changes to those in an age-, sex-, and severity-matched group of AD patients (n = 25) not receiving DBS. Results We observed bilateral hippocampal volume increases in the two patients with the best clinical response to fornix DBS. In one patient, hippocampal volume was preserved three years after diagnosis. Overall, mean hippocampal atrophy was significantly slower in the DBS group compared to the matched AD group, and no matched AD patients demonstrated bilateral hippocampal enlargement. Across DBS patients, hippocampal volume change correlated strongly with hippocampal metabolism and with volume change in the fornix and mammillary bodies, suggesting a circuit-wide effect of stimulation. Deformation-based morphometry in DBS patients revealed local volume expansions in several regions typically atrophied in AD. Conclusion We present the first in-human evidence that, in addition to modulating neural circuit activity, DBS may influence the natural course of brain atrophy in a neurodegenerative disease.
Miniaturized handheld confocal imaging may assist neurosurgeons in detecting infiltrative brain tumor margins during surgery. It may help to avoid sampling error during biopsy of heterogeneous glial neoplasms, with the potential to supplement conventional intraoperative frozen section pathology. Clinical trials are warranted on the basis of these promising initial results.
DBS is now an established symptomatic treatment modality for Parkinson's disease and other movement disorders. Future work will undoubtedly involve establishing new indications and targets in the treatment of movement disorders with further refinements to existing technology. Ultimately, these methods combined with biologically based therapies may catalyze a shift from symptomatic treatment to actually modifying the natural history of neurodegenerative diseases such as Parkinson's disease.
Interest and motivation remain strong for deep brain stimulation for psychiatric disease. Progress will require coordinated efforts by all stakeholders.
The model provides a useful initial framework by which biological mechanisms of invasion and efficacy of potential treatment regimens may be assessed.
Background Many medically-refractory trigeminal neuralgia patients are non-responders to surgical treatment. Few studies have explored how trigeminal nerve characteristics relate to surgical outcome, and none have investigated the relationship between subcortical brain structure and treatment outcomes. Methods We retrospectively studied trigeminal neuralgia patients undergoing surgical treatment with microvascular decompression. Preoperative magnetic resonance imaging was used for manual tracing of trigeminal nerves and automated segmentation of hippocampus, amygdala, and thalamus. Nerve and subcortical structure volumes were compared between responders and non-responders and assessed for ability to predict postoperative pain outcome. Results In all, 359 trigeminal neuralgia patients treated surgically from 2005–2018 were identified. A total of 34 patients met the inclusion criteria (32 with classic and two with idiopathic trigeminal neuralgia). Across all patients, thalamus volume was reduced ipsilateral compared to contralateral to the side of pain. Between responders and non-responders, non-responders exhibited larger contralateral trigeminal nerve volume, and larger ipsilateral and contralateral hippocampus volume. Through receiver-operator characteristic curve analyses, contralateral hippocampus volume correctly classified treatment outcome in 82% of cases (91% sensitive, 78% specific, p = 0.008), and contralateral nerve volume correctly classified 81% of cases (91% sensitive, 75% specific, p < 0.001). Binomial logistic regression analysis showed that contralateral hippocampus and contralateral nerve volumes together classified outcome with 84% accuracy (Nagelkerke R2 = 65.1). Conclusion Preoperative hippocampal and trigeminal nerve volume, measured on standard clinical magnetic resonance images, may predict early non-response to surgical treatment for trigeminal neuralgia. Treatment resistance in medically refractory trigeminal neuralgia may depend on the structural features of both the trigeminal nerve and structures involved in limbic components of chronic pain.
The mouse glioma 261 (GL261) is recognized as an in vivo model system that recapitulates many of the features of human glioblastoma multiforme (GBM). The cell line was originally induced by intracranial injection of 3-methyl-cholantrene into a C57BL/6 syngeneic mouse strain 1 ; therefore, immunologically competent C57BL/6 mice can be used. While we use GL261, the following protocol can be used for the implantation and monitoring of any intracranial mouse tumor model. GL261 cells were engineered to stably express firefly luciferase (GL261-luc). We also created the brighter GL261-luc2 cell line by stable transfection of the luc2 gene expressed from the CMV promoter. C57BL/6-cBrd/cBrd/Cr mice (albino variant of C57BL/6) from the National Cancer Institute, Frederick, MD were used to eliminate the light attenuation caused by black skin and fur. With the use of albino C57BL/6 mice; in vivo imaging using the IVIS Spectrum in vivo imaging system is possible from the day of implantation (Caliper Life Sciences, Hopkinton, MA). The GL261-luc and GL261-luc2 cell lines showed the same in vivo behavior as the parental GL261 cells. Some of the shared histological features present in human GBMs and this mouse model include: tumor necrosis, pseudopalisades, neovascularization, invasion, hypercellularity, and inflammation 1 .Prior to implantation animals were anesthetized by an intraperitoneal injection of ketamine (50 mg/kg), xylazine (5 mg/kg) and buprenorphine (0.05 mg/kg), placed in a stereotactic apparatus and an incision was made with a scalpel over the cranial midline. A burrhole was made 0.1mm posterior to the bregma and 2.3mm to the right of the midline. A needle was inserted to a depth of 3mm and withdrawn 0.4mm to a depth of 2.6mm. Two μl of GL261-luc or GL261-luc2 cells (10 7 cells/ml) were infused over the course of 3 minutes. The burrhole was closed with bonewax and the incision was sutured.Following stereotactic implantation the bioluminescent cells are detectable from the day of implantation and the tumor can be analyzed using the 3D image reconstruction feature of the IVIS Spectrum instrument. Animals receive a subcutaneous injection of 150μg luciferin /kg body weight 20 min prior to imaging. Tumor burden is quantified using mean tumor bioluminescence over time. Tumor-bearing mice were observed daily to assess morbidity and were euthanized when one or more of the following symptoms are present: lethargy, failure to ambulate, hunched posture, failure to groom, anorexia resulting in >10% loss of weight. Tumors were evident in all of the animals on necropsy.
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