Introduction:  Neuromodulation of brain functions can be accomplished in many ways. Alzheimer´s disease (AD) is associated with loss of basal forebrain cholinergic neurons (BFCN’s) and cognitive dysfunction. BFCN’s are dependent on nerve growth factor (NGF) with reduced levels in the AD basal forebrain. Another growth factor, BDNF, is also associated with AD pathogenesis. Previously, we have developed an encapsulated cell biodelivery (ECB) platform and utilized it to stimulate BFCN’s in two cholinergic target sites (Ch2 [nucl. basalis of Meynert] & Ch4) by delivering ß-NGF in 10 AD patients. The technique appears safe and showed tendencies to improved cholinergic function and cognition.  However, more knowledge about factors affecting the NGF release from the encapsulated cells is needed. We here report results from in vitro and in vivo (both animals and human) studies on NGF and BDNF release.  

Methods: The ECB-NGF devices contain a genetically modified cell-line releasing ßNGF. Devices for the first 6 patients contained the NGC0295 cell-line which eventually showed diminished ß-NGF release and low cell survival post-explantation (12-months). Devices in the next 4 patients contained an improved cell-line, (10 x higher ß-NGF release) but with a varied ß-NGF release post explantation (6-months). To investigate factors affecting ß-NGF release from ECB devices, we exposed NGC0211 cells in-vitro to – (1) CSF from patients with AD, Lewy body dementia or subjective cognitive impairment, (2) amyloid-beta (Aß) peptides and inflammatory molecules (features of AD brain), (3) conditioned medium from activated astroglial and microglial cells (glial hyperactivation is common in AD). ß-NGF release and cell survival were measured after these in-vitro exposures, respectively. In addition, devices containing a cell-line releasing BDNF were implanted for three months in hippocampi of a mouse model of AD, the AppNL-G-F mice.

Results: 1: All patients tolerated ECB-NGF therapy well and a subset showed improved cognitive scores and cortical 11C-nicotine binding and reduced brain atrophy rate.

2: When NGC0211 cells were exposed to patient CSF, NGF release was affected but not cell survival. Decrease in NGF release was found to significantly correlate with CSF tau but not with amyloid-beta.

3: In an ongoing study a mouse model of AD (AppNL-G-F) with defects resembling human AD, miniature ECB devices secreting BDNF were implanted in selected hippocampal sites. Implants were well tolerated. BDNF staining appeared prominently close to the probes. Interestingly, BDNF therapy improved the mice´s anxiety in the elevated plus maze and improved outcome in the Y-maze test.

Conclusions: ECB-NGF is safe and accurately delivers therapeutics to targeted brain regions in both patients and mice. Data suggest that local delivery of neurotrophic factors may restore brain functions. Further modifications of the cells and delivery technology are needed to improve the therapeutic outcomes and enable longer duration of ECB- growth factor therapy.

Objective: Major Depression (MD) is a prevalent disease with a high subjective and socioeconomic burden. Despite the effectiveness of classical treatment methods, 20% of patients stay treatment resistant.  For a proportion Deep Brain Stimulation (DBS) might be an option. DBS of the superolateral branch of the medial forebrain bundle (slMFB) emerges as a valid treatment option (1). The stimulation region involving the ventral tegmental area (VTA) points to a role of dopaminergic (DA) transmission in treatment mechanisms and potentially in disease pathology. The focus of this work is the demonstration and analysis of individual DA anatomy (cells, fibers) in subjects who were suspected  having committed suicide.  

Methods: Figure 1 illustrates our general approach. Three human midbrain (aged 55, 62, 36 years) samples were retrieved during autopsy from forensic pathology. The suspected cause of death at time of autopsy was “suicide”. The specimens were formalin fixated and scanned in a Bruker MRI scanner (7T). After histological workup (Nissl stain, HE, Luxol fast blue and TH=tyrosine hydroxylase stain) and cutting, roughly ACPC parallel slices (3 μm) were digitized and joined in MNI space together with a previously developed high resolution fiber tract atlas (n=1) (2). Sub-nuclei of the VTA region (parabrachial pigmented nucleus, PBP; rostral linear nucleus,  Rli;  VTA proper, VTA; paranigral nucleus, PNg; substantia nigra pars compacta, SNc) were identified and marked. TH cell and fiber counts were semi-quantitatively evaluated. Cell and fiber densities were rated as 0=no cells/fibers to 3=high densities of cells/fibers. 

Results: Main results are shown in Figure 2. The parallel demonstration of histological information and TH signal/DA anatomy together with fiber tractographic anatomy in a common space is feasible, allowing for group level analyses. The semi-quantitative analysis showed a marked loss of the TH signal  in the subnucleus VTA proper.  Other subnuclei didn’t show a relevant change. 

Discussion: We have here presented potential hints for a role of TH signal pointing to DA cell/fiber density in the VTA in suicide and potentially MDD. The use of postmortem MRI (7T) as an individual scaffold helps to compensate for tissue distortions which arise through excision, preparational steps and histological handling. These problems need a significant amount of manual interactions. Due to the small sample size and a lack of a true comparison, study results must be regarded with caution. TH signal variations have been attributed to changes in sunlight exposure and might be related to the summer/winter period when death occurred (3). Our sample is too small to draw any conclusions concerning this problem. Whether a TH signal loss is equivalent to DA cell loss and/or is specific for suicide/MDD is a matter of future research.

Conclusion: This work represents our first attempt to investigate the theory of DA cell loss in the human VTA as a cause for suicide/MDD. It therefore represents a study of feasibility.

References:

1. Coenen et al. 2019, 10.1038/s41386-019-0369-9

2. Coenen et al. 2021, 10.1007/s00429-021-02373-x

3. Aumann et al. 2016, 10.1371/journal.pone.0158847

Abstract

Background

Unilateral focused ultrasound ablation of the globus pallidus improved motor symptoms of Parkinson’s disease (PD) in open-label trials. We tested its safety and efficacy in a multicenter, double-blind, sham-controlled randomized trial.

Methods

PD subjects with significant motor complications of medical treatment (characterized by dyskinesias or motor fluctuations) were enrolled and randomly assigned in a 3:1 ratio to focused ultrasound or sham treatment. Subjects were confirmed to have a motor impairment score ≥20 using the Movement Disorders Society Unified Parkinson’s Disease Rating Scale subscale III (MDS UPDRS III) and levodopa responsiveness (defined as a 30% decline in MDS UPDRS III score after levodopa).

            The primary outcome was the number of responders at three months, defined by a pre-specified composite score measuring clinically meaningful reduction in either dyskinesia (defined as ≥3 points decline in the unified dyskinesia rating score (UDysRS) and/or improvement in motor impairment (defined as ≥3 points decline in the MDS UPDRS III score).

Results

Ninety-four subjects were randomly assigned to unilateral globus pallidus focused ultrasound ablation (n=69) or sham treatment (n=25). Sixty-five focused ultrasound and 22 sham subjects completed the primary outcome assessment. 

            Forty-five subjects (69.2%) in the focused ultrasound group were responders in contrast to 7 (31.8%) in the sham group (Odds ratio: 4.8, 95%CI: 1.7-13.6, p=0.003). After focused ultrasound ablation, MDS UPDRS III improved in 19 (29.2% subjects, mean improvement: 49.2%), UDysRS in 8 (12.3% subjects, mean improvement: 66.7%), and both MDS UPDRS III and UDysRS improved in 18 (27.7% subjects, mean improvements: 39.5% and 70.3% respectively). Pallidotomy-related adverse events were mild or moderate and transient.

Conclusions

We report significant improvement in dyskinesia and motor impairment in subjects with Parkinson’s disease undergoing unilateral focused ultrasound ablation of the globus pallidus (Level-I).

Background – Serviceable hearing preservation remains a major issue in the management of vestibular schwannomas (VSs). Authors have postulated that hearing gradually deteriorates following stereotactic radiosurgery. We analyzed data prospectively collected during our 30-year experience with the aim of building a predictive model of individual hearing evolution over time.

Methods – Were included patients with serviceable hearing treated in Marseille by Gammaknife radiosurgery (GKRS) for sporadic VS from July 1992 to December 2017. Hearing status was assessed using the Pure Tone Average (PTA). A mixed linear regression model was used to predict the PTA evolution. Discriminant variables were selected with univariate then multivariate analyses performed on a training data set (70% of the cohort). The accuracy of the resulting model was assessed using a test data set (30% of the cohort).

Results – 1,179 patients were included. Median marginal dose was 11 Gy. Median follow-up was 48 months with 448 patients followed 5+ years, 143 patients followed 10+ years, and some up to 30 years. Along with PTA at GKRS, five variables were selected: hearing complaint, Ohata classification, intracanalicular volume, marginal dose, number of isocenters. The accuracy of the model was 0.73.

Conclusions – This model provides valuable guidance. Out of the 6 predictive variables, the physician may influence up to 4 of them. Early detection and treatment of VSs is required. The marginal dose and number of isocenters may be adapted during treatment planning. Finally, this model can help practitioners to deliver to their patients a more comprehensive information regarding their hearing prognosis.

We present 100 consecutive patients with therapy-refractory obsessive-compulsive disorder (OCD) who underwent deep brain stimulation from 2005-2023 in the Amsterdam University Medical Center. Response to DBS increased from 43% to 60% while changing our electrode targeting strategy from the nucleus accumbens to the ventral part of the anterior limb of the internal capsule (ALIC). The response further increased to 74% when electrodes were implanted in the superolateral branch of the medial forebrain bundle (slMFB) at its course through ALIC. Patients in whom OCD was diagnosed in adulthood tended to respond better than patients with childhood onset (72% versus 56%, respectively). Furthermore, a significant number of non-responders showed a long-lasting response to DBS (up to 12 years) before 'losing' the clinical effect. Besides the different targeting strategies and response rates, a summary of the surgical complications encountered will be presented.

Objective: To characterize the local field potential (LFP) peaks and stimulation mode utilization in patients with Parkinson’s disease (PD) receiving adaptive deep brain stimulation (aDBS) neurostimulators in the real-world data obtained from aDBS Japan Registry.

Background: LFPs, recorded from deep brain stimulation (DBS) electrodes, provide salient biomarkers of pathologic oscillatory activity which could be leveraged for clinical implementation. aDBS, where stimulation amplitude is adjusted according to the power of a pre-selected frequency of interest, is available for commercial use in Japan. However, the data regarding feedback signal characteristics and aDBS mode utilization in a real-world sample are lacking.

Methods: A total of 101 patients (age: 63.7[31.0-82.0] years; sex: 57 females (56.4%); disease duration: 13.0[3.0-26.0] years; 78 therapy naïve) were included in this interim analysis of a prospective, non-randomized, observational, open-labeled, and multi-center registry. Patients were either programmed to continuous DBS (cDBS), single-threshold (ST) aDBS, or dual-threshold (DT) aDBS according to site standard of care. LFPs were recorded using Percept^TM PC with BrainSense^TM Technology. LFP peaks were identified from automated algorithms in the frequency range of 8-30 Hz and are reported for 47 patients with bilateral STN recordings.

Results: STN LFP peaks were detected in 73/91 total recordings (80%), three hemispheres did not have omnidirectional LFP recordings. Peak power and frequency were a median of 1.66 [interquartile range: 1.20-1.30] uVp and 14.65 [10.74-19.53] Hz, respectively. cDBS was activated on a median of 7 [4-22] days and 0 [0-0] days after device implant for therapy naïve (N=63) and replacement patients (N=18), respectively. aDBS, of either mode, was activated on a median of 56 [8-111] and 41 [20-43] days after device implant for therapy naïve (N=28, 44.4%) and replacement patients (N=5, 27.8%). Overall, the most prevalent aDBS mode selected at first aDBS activation was DT (31/33, 93.9%).

Conclusion: This analysis reports the automated peak detection and programming characteristics from the largest, real-world cohort of aDBS for the treatment of PD. We found 80% of hemispheres contained a peak which, on average, fell within the low-beta (13-20 Hz) range. Moreover, aDBS was used in about 40% of patients with STN-DBS and more than 90% was DT mode. These early results provide early evidence of real-world aDBS feasibility. However, continued research is needed to determine aDBS efficacy in a real-world sample.

Background: Anthropology is the study of human societies and cultures and their development. Anthropology of deep brain stimulation (DBS) refers to the study of the origin of DBS and of DBS -related culture and behavior beyond its impact on symptoms of diseases.

Objective: To study the ethno-geographic origins of DBS, and DBS-induced impact on clinicians and scientists and the influence of DBS on Society at large. 

Material & Methods: The authors scrutinized the geo-ethnic origins of the pioneers of modern DBS and evaluated the impact of DBS on clinicians, on healthcare and on Society at large.

Results: Modern DBS was born in 1987 in Grenoble thanks to the fruitful collaboration between a Jewish neurologist with Bessarabian origins and a neurosurgeon of Algerian descent. In 1990, a Hebrew neuroscientist discovered the benefit of lesioning the subthalamic nucleus (STN) in an animal model of Parkinson´s disease (PD), which was confirmed in 1991 by another scientist of Bengladeshi descent. In 1993 a Moroccan neurophysiologist demonstrated the benefit of DBS of the STN on a Parkinsonian animal model, leading to the first human application of STN DBS in a PD patient by the initial pioneers of modern DBS. Clinical DBS, especially STN DBS, that started as a “folie à deux” became a true “folie en masse” with the establishment in many centers of large multidisciplinary teams comprising also DBS nurses, neurophysiologists, neuropsychologists, neuroradiologists, neuroscientists, neuro-engineers, neuro-ethicists, speech therapists and others, assembling all kinds of genders, faith, ethnicities, ages and nationalities. Especially neurologists have become enthusiastic about surgery and contributed actively in the operating room at any time of day or night, assisting the neurosurgeons, and took on new laborious tasks of programming ever more complicated DBS systems. Publications sky-rocketed on PubMed and elsewhere, and neurologists became much happier and more dedicated to DBS which soon spread to the world and impacted positively the economy of many countries: Unemployment rates decreased with the increase in recruitment of clinicians and nurses, research fellows and scientists, as well as the establishment of new DBS companies. This led to promotion of many more international conferences and meetings than before the DBS era, which in turn benefitted transportation companies, hotels, restaurants, shops, medias, etc... With the ever-increasing indications and brain targets for DBS, more positive global impact on societies is expected.

Conclusions: Modern DBS was born in the spirit of Al-Andalus. DBS has generated a true global benefit on many aspects of Society, well beyond its established clinical benefits on symptoms of various diseases.