Boris Rosin

Closed-Loop Deep Brain Stimulation Is Superior in Ameliorating Parkinsonism

Continuous high-frequency deep brain stimulation (DBS) is a widely used therapy for advanced Parkinsons 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.

Encoding of Probabilistic Rewarding and Aversive Events by Pallidal and Nigral Neurons

Previous studies have rarely tested whether the activity of high-frequency discharge (HFD) neurons of the basal ganglia (BG) is modulated by expectation, delivery, and omission of aversive events. Therefore the full value domain encoded by the BG network is still unknown. We studied the activity of HFD neurons of the globus pallidus external segment (GPe, n=310), internal segment (GPi, n=149), and substantia nigra pars reticulata (SNr, n=145) in two monkeys during a classical conditioning task with cues predicting the probability of food, neutral, or airpuff outcomes. The responses of BG HFD neurons were long-lasting and diverse with coincident increases and decreases in discharge rate. The population responses to reward-related events were larger than the responses to aversive and neutral-related events. The latter responses were similar, except for the responses to actual airpuff delivery. The fraction of responding cells was larger for reward-related events, with better discrimination between rewarding and aversive trials in the responses with an increase rather than a decrease in discharge rate. GPe and GPi single units were more strongly modulated and better reflected the probability of reward- than aversive-related events. SNr neurons were less biased toward the encoding of the rewarding events, especially during the outcome epoch. Finally, the latency of SNr responses to all predictive cues was shorter than the latency of pallidal responses. These results suggest preferential activation of the BG HFD neurons by rewarding compared with aversive events.

Low-Pass Filter Properties of Basal Ganglia–Cortical–Muscle Loops in the Normal and MPTP Primate Model of Parkinsonism

Oscillatory bursting activity is commonly found in the basal ganglia (BG) and the thalamus of the parkinsonian brain. The frequency of these oscillations is often similar to or higher than that of the parkinsonian tremor, but their relationship to the tremor and other parkinsonian symptoms is still under debate. We studied the frequency dependency of information transmission in the cortex–BG and cortex–periphery loops by recording simultaneously from multiple electrodes located in the arm-related primary motor cortex (MI) and in the globus pallidus (GP) of two vervet monkeys before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment and induction of parkinsonian symptoms. We mimicked the parkinsonian bursting oscillations by stimulating with 35 ms bursts given at different frequencies through microelectrodes located in MI or GP while recording the evoked neuronal and motor responses. In the normal state, microstimulation of MI or GP does not modulate the discharge rate in the other structure. However, the functional-connectivity between MI and GP is greatly enhanced after MPTP treatment. In the frequency domain, GP neurons usually responded equally to 1–15 Hz stimulation bursts in both states. In contrast, MI neurons demonstrated low-pass filter properties, with a cutoff frequency above 5 Hz for the MI stimulations, and below 5 Hz for the GP stimulations. Finally, muscle activation evoked by MI microstimulation was markedly attenuated at frequencies higher than 5 Hz. The low-pass properties of the pathways connecting GP to MI to muscles suggest that parkinsonian tremor is not directly driven by the BG 5–10 Hz burst oscillations despite their similar frequencies.

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.

Physiology and pathophysiology of the basal ganglia—thalamo—cortical networks

Low-frequency resting tremor is one of the cardinal signs of Parkinsons disease (PD) and occurs also in some of its animal models. Current physiological studies and models of the basal ganglia indicate that changes of discharge pattern and synchronization of basal ganglia neurons rather than modification in their discharge rate are crucial to the pathophysiology of PD. However, parkinsonian tremor is not strictly correlated with the synchronous oscillations in the basal ganglia networks. We therefore suggest that abnormal basal ganglia output enforces abnormal thalamo-cortical processing leading to akinesia, the main negative symptom of Parkinsons disease. The parkinsonian positive motor signs, such as tremor and rigidity, most likely evolve as a downstream compensatory mechanism.

Original articleGenetics 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.

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.

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.

Chapter 38 – Pathological Synchrony of Basal Ganglia-Cortical Networks in the Systemic MPTP Primate Model of Parkinson's Disease

Publisher Summary This chapter reviews that the core pathology of PD is degeneration of the dopamine neurons in the midbrain and the resulting depletion of striatal dopamine. The striatum is the major input stage of the basal ganglia, receiving input from the cerebral cortex and thalamus, and projecting directly and indirectly to the output stages of the basal ganglia – the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). The dopamine precursor l-DOPA remains the gold standard for the treatment of PD. However, long-term use of l-DOPA is associated with the development of motor complications. It discusses that the multi-stage therapy of Parkinsons disease (PD), from dopamine replacement methods to modulation of the activity of the basal ganglia structures using deep Brain Stimulation DBS, reinstates interest in identifying the critical features of abnormal basal ganglia activity that follow striatal dopamine depletion and lead to the symptoms. The chapter summarizes the main physiological findings in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) primate model of PD, and compares them to the recent physiological findings in human patients. There is an accumulation of data linking excessive synchrony at low frequencies in basal ganglia-thalamo-cortical loops to impaired motor processing in PD. Whether synchronization is an epiphenomenon or truly pathogenic in PD, it provides a clear biological marker for the disease process. Recent studies indicate the differential roles or correlates of the distinctive bands of oscillatory activity in the pathogenesis of PD. It suggests that amelioration of specific domains of basal ganglia-cortical synchronized oscillatory activity could form the basis for future closed-loop stimulation regimes for human PD patients.

Closed-loop DBS in the non-human primate model of Parkinsonism

High-frequency deep brain stimulation (DBS) is a widely used therapy for advanced Parkinson’s disease (PD) management. However, the mechanisms by which DBS exerts its alleviating effect remain to be described. Furthermore, due to its non-adaptive nature, standard DBS is not ideally suited for the treatment of this highly dynamic and progressive disorder. We have devised several closed-loop stimulation strategies for PD and tested them in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate model of PD. These included stimulation of the internal pallidal segment (GPi) according to a predefined trigger in the ongoing neuronal activity. Application of pallido-pallidal closed-loop stimulation leads to dissociation between changes in basal ganglia (BG) discharge rates and patterns, providing insights into PD pathophysiology. Notably, 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. These results demonstrate that 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.