Best Disease: Global Mutations Review, Genotype-Phenotype Correlation, and Prevalence Analysis in the Israeli Population.

Purpose: To review all reported disease-causing mutations in BEST1, perform genotype-phenotype correlation, and estimate disease prevalence in the Israeli population. Methods: Medical records of patients diagnosed with Best disease and allied diseases from nine Israeli medical centers over the past 20 years were collected, as were clinical data including ocular findings, electrophysiology results, and retina imaging. Mutation detection involved mainly whole exome sequencing and candidate gene analysis. Demographic data were obtained from the Israeli Bureau of Statistics (January 2023). A bibliometric study was also conducted to gather mutation data from online sources. Results: A total of 134 patients were clinically diagnosed with Best disease and related conditions. The estimated prevalence of Best disease was calculated to be 1 in 127,000, with higher rates among Arab Muslims (1 in 76,000) than Jews (1 in 145,000). Genetic causes were identified in 76 individuals (57%), primarily showing autosomal-dominant inheritance due to BEST1 mutations (58 patients). Critical conserved domains were identified consisting of a high percentage of dominant missense mutations, primarily in transmembrane domains and the intracellular region (Ca2+ binding domain) of the BEST1 protein. Conclusions: This study represents the largest cohort of patients with Best disease reported in Israel and globally. The prevalence in Israel is akin to that in Denmark but is lower than that in the United States. Critical conserved domains within the BEST1 protein are pivotal for normal functioning, and even minor missense alterations in these areas lead to a dominant disease manifestation. Genetic testing is indispensable as the gold standard for Best disease diagnosis due to the variable clinical presentation of the disease.

An Optical Coherence Tomography-Based Measure as an Independent Estimate of Retinal Function in Retinitis Pigmentosa.

BACKGROUND: With the clinical advances in the field of gene therapy, the development of objective measures of visual function of patients with inherited retinal dystrophies (IRDs) is of utmost importance. Here, we propose one such measure. METHODS: We retrospectively analyzed data from a cohort of 194 eyes of 97 genetically diagnosed patients with retinitis pigmentosa (RP), the most common IRD, followed at the UPMC Vision Institute. The analyzed data included the reflectivity ratio (RR) of the retinal nerve fiber layer (RNFL) to that of the entire retina, visual acuity (VA) and the thickness of the retinal outer nuclear layer (ONL) and the RNFL. RESULTS: There was a strong positive correlation between the RR and VA. Both VA and the RR were negatively correlated with disease duration; VA, but not the RR, was negatively correlated with age. The RR correlated with the ONL but not with the RNFL thickness or the intraocular pressure. Age, RR, disease duration and ONL thickness were found to be independent predictors of VA by multivariate analysis. CONCLUSION: The OCT RR could serve as an independent predictor of visual acuity, and by extension of retinal function, in genetically diagnosed RP patients. Such objective measures can be of great value in patient selection for therapeutic trials.

Tuned to Tremor: Increased Sensitivity of Cortico-Basal Ganglia Neurons to Tremor Frequency in the MPTP Nonhuman Primate Model of Parkinson's Disease.

Rest tremor is one of the most prominent clinical features of Parkinson's disease (PD). Here, we hypothesized that cortico-basal ganglia neurons tend to fire in a pattern that matches PD tremor frequency, suggesting a resonance phenomenon. We recorded spiking activity in the primary motor cortex (M1) and globus pallidus external segment of 2 female nonhuman primates, before and after parkinsonian state induction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The arm of nonhuman primates was passively rotated at seven different frequencies surrounding and overlapping PD tremor frequency. We found entrainment of the spiking activity to arm rotation and a significant sharpening of the tuning curves in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine state, with a peak response at frequencies that matched the frequency of PD tremor. These results reveal increased sensitivity of the cortico-basal ganglia network to tremor frequency and could indicate that this network acts not only as a tremor switch but is involved in setting its frequency.SIGNIFICANCE STATEMENT Tremor is a prominent clinical feature of Parkinson's disease; however, its underlying pathophysiology is still poorly understood. Using electrophysiological recordings of single cortico-basal ganglia neurons before and after the induction of a parkinsonian state, and in response to passive arm rotation, this study reports increased sensitivity to tremor frequency in Parkinson's disease. We found sharpening of the population tuning to the midrange of the tested frequencies (1-13.3 Hz) in the healthy state that further increased in the parkinsonian state. These results hint at the increased frequency-tuned sensitivity of cortico-basal ganglia neurons and suggest that they tend to resonate with the tremor.

Current Status of Clinical Trials Design and Outcomes in Retinal Gene Therapy.

With the rapid expansion of methods encompassed by the term gene therapy, new trials exploring the safety and efficacy of these methods are initiated more frequently. As a result, important questions arise pertaining the design of these trials and patient participation. One of the most important aspects of any clinical trial is the ability to measure the trial's outcome in a manner that will reflect the effect of the treatment and allow its quantification, whether the trial is aimed at preservation or restoration of retinal cells (photoreceptors and others), vision, or both. Here we will review the existing methods for quantification of trial outcomes, stressing the importance of assessing the participant's visual function and not just visual acuity. We will also describe the key considerations in trial design. Finally, as patient safety remains the primary concern in any trial participation, we will outline the key principles in that regard.

Coagulase-negative staphylococcal endophthalmitis: clinical severity and outcomes based on speciation.

OBJECTIVE: To identify characteristics and visual outcomes of coagulase-negative staphylococcal (CoNS) endophthalmitis in the era after the Endophthalmitis Vitrectomy Study. DESIGN: Single-centre retrospective analysis. PARTICIPANTS: Forty-two samples from 40 patients with documented CoNS endophthalmitis. METHODS: Visual acuity outcomes of CoNS endophthalmitis were assessed in relation to species and type of treatment instituted (i.e., pars plana vitrectomy [PPV] versus vitreous tap and injection of intravitreal antibiotics [T&I]) on 42 samples from 40 patients. RESULTS: Staphylococcus epidermidis was the most prevalent CoNS in our study. Cataract surgery and intravitreal injections were the most common sources for acute CoNS endophthalmitis. Eyes presenting with hand motion or better vision had similar mean final vision after either intravitreal antibiotics or PPV, whereas those with light perception or worse vision at onset had better outcomes after PPV only. Subanalysis showed that patients with S. epidermidis endophthalmitis (n = 39 eyes) had similar visual outcomes with either intravitreal injections or PPV regardless of visual acuity. Hypopyon and vitritis are not always present. CONCLUSIONS: Patients with S. epidermidis endophthalmitis may benefit similarly from either early vitrectomy or intravitreal antibiotic injections regardless of visual acuity. This finding may be a supplement to the complements the management standards set forth by the Endophthalmitis Vitrectomy Study.

Batch-balanced focal loss: a hybrid solution to class imbalance in deep learning.

Purpose: To validate the effectiveness of an approach called batch-balanced focal loss (BBFL) in enhancing convolutional neural network (CNN) classification performance on imbalanced datasets. Materials and Methods: BBFL combines two strategies to tackle class imbalance: (1) batch-balancing to equalize model learning of class samples and (2) focal loss to add hard-sample importance to the learning gradient. BBFL was validated on two imbalanced fundus image datasets: a binary retinal nerve fiber layer defect (RNFLD) dataset (n=7,258) and a multiclass glaucoma dataset (n=7,873). BBFL was compared to several imbalanced learning techniques, including random oversampling (ROS), cost-sensitive learning, and thresholding, based on three state-of-the-art CNNs. Accuracy, F1-score, and the area under the receiver operator characteristic curve (AUC) were used as the performance metrics for binary classification. Mean accuracy and mean F1-score were used for multiclass classification. Confusion matrices, t-distributed neighbor embedding plots, and GradCAM were used for the visual assessment of performance. Results: In binary classification of RNFLD, BBFL with InceptionV3 (93.0% accuracy, 84.7% F1, 0.971 AUC) outperformed ROS (92.6% accuracy, 83.7% F1, 0.964 AUC), cost-sensitive learning (92.5% accuracy, 83.8% F1, 0.962 AUC), and thresholding (91.9% accuracy, 83.0% F1, 0.962 AUC) and others. In multiclass classification of glaucoma, BBFL with MobileNetV2 (79.7% accuracy, 69.6% average F1 score) outperformed ROS (76.8% accuracy, 64.7% F1), cost-sensitive learning (78.3% accuracy, 67.8.8% F1), and random undersampling (76.5% accuracy, 66.5% F1). Conclusion: The BBFL-based learning method can improve the performance of a CNN model in both binary and multiclass disease classification when the data are imbalanced.

Lifting the iron curtain of vision.

Ocular and specifically retinal toxicities of systemic medications are prevalent and encompass many disease modalities. For many of these pharmaceuticals, established follow-up protocols are in place to ensure timely detection and cessation of therapy. However, while for some disorders, cessation of therapy is a viable option due to existing treatment alternatives, for some others cessation of treatment can be life threatening and/or shorten the patient's life expectancy. Such is the case for iron chelating agents used in transfusion-dependent patients of Thalassemia, of which deferoxamine (DFO) is the most widely used. In their recent article in EMBO Molecular Medicine, Kong et al (2023) addressed the issue of DFO-induced retinal toxicity used both in vivo and in vitro techniques. Their study suggests a potentially protective role for α-ketoglutarate (AKG) supplementation against DFO toxicity.

Identification of autosomal recessive novel genes and retinal phenotypes in members of the solute carrier (SLC) superfamily.

PURPOSE: This study aimed to investigate the clinical and genetic aspects of solute carrier (SLC) genes in inherited retinal diseases (IRDs). METHODS: Exome sequencing data were filtered to identify pathogenic variants in SLC genes. Analysis of transcript and protein expression was performed on fibroblast cell lines and retinal sections. RESULTS: Comprehensive analysis of 433 SLC genes in 913 exome sequencing IRD samples revealed homozygous pathogenic variants in 6 SLC genes, including 2 candidate novel genes, which were 2 variants in SLC66A1, causing autosomal recessive retinitis pigmentosa (ARRP), and a variant in SLC39A12, causing autosomal recessive mild widespread retinal degeneration with marked macular involvement. In addition, we present 4 families with ARRP and homozygous null variants in SLC37A3 that were previously suggested to cause retinitis pigmentosa, 2 of which cause exon skipping. The recently reported SLC4A7- c.2007dup variant was found in 2 patients with ARRP resulting in the absence of protein. Finally, variants in SLC24A1 were found in 4 individuals with either ARRP or congenital stationary night blindness. CONCLUSION: We report on SLC66A1 and SLC39A12 as candidate novel IRD genes, establish SLC37A3 pathogenicity, and provide further evidence of SLC4A7 as IRD genes. We extend the phenotypic spectrum of SLC24A1 and suggest that its ARRP phenotype may be more common than previously reported.

Autoimmune retinopathy: clinical, electrophysiological, and immunological features in nine patients with long-term follow-up.

PURPOSE: We aim to report on the clinical, imaging, immunological, and electrophysiological features of patients with autoimmune retinopathy (AIR) with long-term follow-up. METHODS: Single-center, retrospective study of a consecutive group of AIR patients treated in a tertiary academic medical center. RESULTS: Included were nine patients with a mean ± SD age at presentation of 65 ± 13 years and a median follow-up of 63 months (range 18-120). Five patients were known to have cancer. Median interval between onset of ocular symptoms and diagnosis of AIR was 36 months. Mean baseline and final LogMAR visual acuity were 0.72 ± 0.9 and 1.1 ± 1.2, respectively (p = 0.17). The most common funduscopic findings included optic atrophy and bone-spicule-like pigmentation. Thinning of the nerve fiber layer was the most frequent optical coherence tomographic abnormality. Electroretinographic (ERG) recordings demonstrated variably reduced cone- and rod-derived amplitudes in the majority of eyes at presentation. The most commonly detected anti-retinal antibody was anti-α-enolase. Treatment included immunomodulatory therapy and plasmapheresis. ERG tests showed stability in 64% of eyes throughout the treatment period. CONCLUSION: This study highlights the importance of maintaining a high index of suspicion of AIR, particularly in late middle-aged and elderly patients with "unexplained" visual loss, in light of the non-specific posterior segment signs and the inconsistency of the routinely used ancillary tests.

Broadening INPP5E phenotypic spectrum: detection of rare variants in syndromic and non-syndromic IRD.

Pathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype-phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD.

How do the blind 'see'? The role of spontaneous brain activity in self-generated perception.

Spontaneous activity of the human brain has been well documented, but little is known about the functional role of this ubiquitous neural phenomenon. It has previously been hypothesized that spontaneous brain activity underlies unprompted (internally generated) behaviour. We tested whether spontaneous brain activity might underlie internally-generated vision by studying the cortical visual system of five blind/visually-impaired individuals who experience vivid visual hallucinations (Charles Bonnet syndrome). Neural populations in the visual system of these individuals are deprived of external input, which may lead to their hyper-sensitization to spontaneous activity fluctuations. To test whether these spontaneous fluctuations can subserve visual hallucinations, the functional MRI brain activity of participants with Charles Bonnet syndrome obtained while they reported their hallucinations (spontaneous internally-generated vision) was compared to the: (i) brain activity evoked by veridical vision (externally-triggered vision) in sighted controls who were presented with a visual simulation of the hallucinatory streams; and (ii) brain activity of non-hallucinating blind controls during visual imagery (cued internally-generated vision). All conditions showed activity spanning large portions of the visual system. However, only the hallucination condition in the Charles Bonnet syndrome participants demonstrated unique temporal dynamics, characterized by a slow build-up of neural activity prior to the reported onset of hallucinations. This build-up was most pronounced in early visual cortex and then decayed along the visual hierarchy. These results suggest that, in the absence of external visual input, a build-up of spontaneous fluctuations in early visual cortex may activate the visual hierarchy, thereby triggering the experience of vision.

Surface Modification by Nano-Structures Reduces Viable Bacterial Biofilm in Aerobic and Anaerobic Environments.

Bacterial biofilm formation on wet surfaces represents a significant problem in medicine and environmental sciences. One of the strategies to prevent or eliminate surface adhesion of organisms is surface modification and coating. However, the current coating technologies possess several drawbacks, including limited durability, low biocompatibility and high cost. Here, we present a simple antibacterial modification of titanium, mica and glass surfaces using self-assembling nano-structures. We have designed two different nano-structure coatings composed of fluorinated phenylalanine via the drop-cast coating technique. We investigated and characterized the modified surfaces by scanning electron microscopy, X-ray diffraction and wettability analyses. Exploiting the antimicrobial property of the nano-structures, we successfully hindered the viability of Streptococcus mutans and Enterococcus faecalis on the coated surfaces in both aerobic and anaerobic conditions. Notably, we found lower bacteria adherence to the coated surfaces and a reduction of 86-99% in the total metabolic activity of the bacteria. Our results emphasize the interplay between self-assembly and antimicrobial activity of small self-assembling molecules, thus highlighting a new approach of biofilm control for implementation in biomedicine and other fields.

CASE REPORT OF SEVERE PROLIFERATIVE RETINOPATHY IN A PATIENT WITH CONGENITAL LIPODYSTROPHY.

PURPOSE: A case report of a patient with severe proliferative retinopathy due to congenital lipodystrophy. METHODS: We reviewed the medical history, imaging, and surgical procedures of a 25-year-old woman with a history of congenital lipodystrophy, presenting with bilateral combined tractional and exudative retinal detachment, poorly controlled diabetes mellitus, and extreme dislipidemia. RESULTS: The patient underwent retinal detachment repair surgery both eyes. On the last follow-up, both retinae were flat, and visual acuity had improved in the right eye to J3 for near and finger counting 3 m for distance. CONCLUSION: Surgery combining pars plana vitrectomy and scleral bucking successfully flattened both retinae and significantly improved visual acuity in one eye in this case of bilateral retinal detachment with combined tractional and exudative components in a patient with congenital lipodystrophy. Surgical control of retinal complications is thus possible, provided there is adequate control of the underlying risk factors.

The combination of whole-exome sequencing and clinical analysis allows better diagnosis of rare syndromic retinal dystrophies.

PURPOSE: To identify the accurate clinical diagnosis of rare syndromic inherited retinal diseases (IRDs) based on the combination of clinical and genetic analyses. METHODS: Four unrelated families with various autosomal recessive syndromic inherited retinal diseases were genetically investigated using whole-exome sequencing (WES). RESULTS: Two affected subjects in family MOL0760 presented with a distinctive combination of short stature, developmental delay, congenital mental retardation, microcephaly, facial dysmorphism and retinitis pigmentosa (RP). Subjects were clinically diagnosed with suspected Kabuki syndrome. WES revealed a homozygous nonsense mutation (c.5492dup, p.Asn1831Lysfs*8) in VPS13B that is known to cause Cohen syndrome. The index case of family MOL1514 presented with both RP and liver dysfunction, suspected initially to be related. WES identified a homozygous frameshift mutation (c.1787_1788del, p.His596Argfs*47) in AGBL5, associated with nonsyndromic RP. The MOL1592 family included three affected subjects with crystalline retinopathy, skin ichthyosis, short stature and congenital adrenal hypoplasia, and were found to harbour a homozygous nonsense mutation (c.682C>T, p.Arg228Cys) in ALDH3A2, reported to cause Sjögren-Larsson syndrome (SLS). In the fourth family, SJ002, two siblings presented with hypotony, psychomotor delay, dysmorphic facial features, pathologic myopia, progressive external ophthalmoplegia and diffuse retinal atrophy. Probands were suspected to have atypical Kearns-Sayre syndrome, but were diagnosed with combined oxidative phosphorylation deficiency-20 due to a novel suspected missense variant (c.1691C>T, p.Ala564Val) in VARS2. CONCLUSION: Our findings emphasize the important complement of WES and thorough clinical investigation in establishing precise clinical diagnosis. This approach constitutes the basis for personalized medicine in rare IRDs.

Ketamine induced converged synchronous gamma oscillations in the cortico-basal ganglia network of nonhuman primates.

N-methyl-d-aspartate (NMDA) antagonists are widely used in anesthesia, pain management, and schizophrenia animal model studies, and recently as potential antidepressants. However, the mechanisms underlying their anesthetic, psychotic, cognitive, and emotional effects are still elusive. The basal ganglia (BG) integrate input from different cortical domains through their dopamine-modulated connections to achieve optimal behavior control. NMDA antagonists have been shown to induce gamma oscillations in human EEG recordings and in rodent cortical and BG networks. However, network relations and implications to the primate brain are still unclear. We recorded local field potentials (LFPs) simultaneously from the primary motor cortex (M1) and the external globus pallidus (GPe) of four vervet monkeys (26 sessions, 97 and 76 cortical and pallidal LFPs, respectively) before and after administration of ketamine (NMDA antagonist, 10 mg/kg im). Ketamine induced robust, spontaneous gamma (30-50 Hz) oscillations in M1 and GPe. These oscillations were initially modulated by ultraslow oscillations (~0.3 Hz) and were highly synchronized within and between M1 and the GPe (mean coherence magnitude = 0.76, 0.88, and 0.41 for M1-M1, GPe-GPe, and M1-GPe pairs). Phase differences were distributed evenly around zero with broad and very narrow distribution for the M1-M1 and GPe-GPe pairs (-3.5 ± 31.8° and -0.4 ± 6.0°), respectively. The distribution of M1-GPe phase shift was skewed to the left with a mean of -18.4 ± 20.9°. The increased gamma coherence between M1 and GPe, two central stages in the cortico-BG loops, suggests a global abnormal network phenomenon with a unique spectral signature, which is enabled by the BG funneling architecture.NEW & NOTEWORTHY This study is the first to show spontaneous gamma oscillations under NMDA antagonist in nonhuman primates. These oscillations appear in synchrony in the cortex and the basal ganglia. Phase analysis refutes the confounding effects of volume conduction and supports the funneling and amplifying architecture of the cortico-basal ganglia loops. These results suggest an abnormal network phenomenon with a unique spectral signature that could account for pathological mental and neurological states.

Trends of Bacterial Keratitis Culture Isolates in Jerusalem; a 13- Years Analysis.

PURPOSE: To describe the trends in pathogens and antibacterial resistance of corneal culture isolates in infectious keratitis during a period of 13 years at Hadassah-Hebrew University Medical Center. METHODS: A Retrospective analysis of bacterial corneal isolates was performed during the months of January 2002 to December 2014 at Hadassah Hebrew University Medical Center. Demographics, microbiological data and antibiotic resistance and sensitivity were collected. RESULTS: A total of 943 corneal isolates were analyzed during a 13 year period. A total of 415 positive bacterial cultures and 37 positive fungal cultures were recovered, representing 48% of the total cultures. The Annual incidence was 34.78 ± 6.54 cases. The most common isolate was coagulase-negative staphylococcus (32%), which had a significant decrease in trend throughout the study period (APC = -8.1, p = 0.002). Methicillin-resistant Staphylococcus aureus (MRSA) appears to have a decrease trend (APC = -31.2, P = 0.5). There was an increase in the resistance trend of coagulase-negative staphylococci to penicillin (APC = 5.0, P = <0.001). None of the pathogens had developed any resistance to Vancomycin. (P = 0.88). CONCLUSIONS: Coagulase negative staphylococci were the predominant bacteria isolated from patients with keratitis. There was no significant change in the annual incidence of cases of bacterial keratitis seen over the past 13 years. Keratitis caused by MRSA appeared to decrease in contrast to the reported literature.

Genetics and Disease Expression in the CNGA3 Form of Achromatopsia: Steps on the Path to Gene Therapy.

PURPOSE: Achromatopsia (ACHM) is a congenital, autosomal recessive retinal disease that manifests cone dysfunction, reduced visual acuity and color vision, nystagmus, and photoaversion. Five genes are known causes of ACHM. The present study took steps toward performing a trial of gene therapy in ACHM by characterizing the genetics of ACHM in Israel and the Palestinian Territories and analyzing retinal function and structure in CNGA3 ACHM patients from the Israeli-Palestinian population and US patients with other origins. DESIGN: Case series study. PARTICIPANTS: Patients with clinically suspected ACHM, cone dysfunction phenotypes, and unaffected family members were included. The protocol was approved by the local institutional review board and informed consent was obtained from all participants. METHODS: Genetic analyses included homozygosity mapping and exome sequencing. Phenotype was assessed with electroretinography (ERG), optical coherence tomography, psychophysics, and photoaversion testing. MAIN OUTCOME MEASURES: Single nucleotide polymorphism microarray, exome analysis, DNA sequence analysis, visual function testing including ERG, and photoaversion. RESULTS: We identified 148 ACHM patients from 57 Israeli and Palestinian families; there were 16 CNGA3 mutations (5 novel) in 41 families and 5 CNGB3 mutations (1 novel) in 8 families. Two CNGA3 founder mutations underlie >50% of cases. These mutations lead to a high ACHM prevalence of ∼1:5000 among Arab-Muslims residing in Jerusalem. Rod ERG abnormalities (in addition to cone dysfunction) were detected in 59% of patients. Retinal structure in CNGA3 ACHM patients revealed persistent but abnormal foveal cones. Under dark- and light-adapted conditions, patients use rod-mediated pathways. Photoaversion was readily demonstrated with transition from the dark to a dim light background. CONCLUSIONS: Among Israeli and Palestinian patients, CNGA3 mutations are the leading cause of ACHM. Retinal structural results support the candidacy of CNGA3 ACHM for clinical trials for therapy of cone photoreceptors. Efficacy outcome measures would include chromatic light-adapted psychophysics, with attention to the photoreceptor basis of the response, and quantitation of photoaversion.

Closed-loop deep brain stimulation is superior in ameliorating parkinsonism.

Continuous high-frequency deep brain stimulation (DBS) is a widely used therapy for advanced Parkinson's disease (PD) management. However, the mechanisms underlying DBS effects remain enigmatic and are the subject of an ongoing debate. Here, we present and test a closed-loop stimulation strategy for PD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of PD. Application of pallidal closed-loop stimulation leads to dissociation between changes in basal ganglia (BG) discharge rates and patterns, providing insights into PD pathophysiology. Furthermore, cortico-pallidal closed-loop stimulation has a significantly greater effect on akinesia and on cortical and pallidal discharge patterns than standard open-loop DBS and matched control stimulation paradigms. Thus, closed-loop DBS paradigms, by modulating pathological oscillatory activity rather than the discharge rate of the BG-cortical networks, may afford more effective management of advanced PD. Such strategies have the potential to be effective in additional brain disorders in which a pathological neuronal discharge pattern can be recognized.

Neighboring Pallidal Neurons Do Not Exhibit more Synchronous Oscillations than Remote Ones in the MPTP Primate Model of Parkinson's Disease.

In the healthy primate, neurons of the external and internal segments of the globus pallidus (GP) present a primarily irregular firing pattern, and a negligible level of synchrony is observed between pairs of neurons. This holds even for neighboring cells, despite their higher probability to receive common inputs and to innervate each other via lateral connectivity. In the Parkinsonian primate, this changes drastically, and many pairs of GP cells show synchronous oscillations. To address the relation between distance and synchrony in the Parkinsonian state, we compared the synchrony of discharge of close pairs of neurons, recorded by the same electrode, with remote pairs, recorded by different ones. However, spike trains of neighboring cells recorded by the same extracellular electrode exhibit the shadowing effect; i.e., lack of detection of spikes that occur within a few milliseconds of each other. Here, we demonstrate that the shadowing artifact can both induce apparent correlations between non-correlated neurons, as well as conceal existing correlations between neighboring ones. We therefore introduced artificial shadowing in the remote pairs, similar to the effect we observed in the close ones. After the artificial shadowing, neighboring cells did not show a higher tendency to oscillate synchronously than remote ones. On the contrary, the average percentage (over all sessions) of artificially shadowed remote pairs exhibiting synchronous oscillations was 35.4% compared to 17.2% in the close ones. Similar trend was found when the unshadowed remote pairs were separated according to the estimated distance between electrode tips: 29.9% of pairs at approximate distance of less than 750 µm were significantly synchronized, in comparison with 28.5% of the pairs whose distance was more than 750 µm. We conclude that the synchronous oscillations in the GP of MPTP treated primates are homogenously distributed.