Subthalamic nucleus deep brain stimulation driven by primary motor cortex γ2 activity in parkinsonian monkeys.

In parkinsonism, subthalamic nucleus (STN) electrical deep brain stimulation (DBS) improves symptoms, but may be associated with side effects. Adaptive DBS (aDBS), which enables modulation of stimulation, may limit side effects, but limited information is available about clinical effectiveness and efficaciousness. We developed a brain-machine interface for aDBS, which enables modulation of stimulation parameters of STN-DBS in response to γ2 band activity (80-200 Hz) of local field potentials (LFPs) recorded from the primary motor cortex (M1), and tested its effectiveness in parkinsonian monkeys. We trained two monkeys to perform an upper limb reaching task and rendered them parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Bipolar intracortical recording electrodes were implanted in the M1, and a recording chamber was attached to access the STN. In aDBS, the M1 LFPs were recorded, filtered into the γ2 band, and discretized into logic pulses by a window discriminator, and the pulses were used to modulate the interval and amplitude of DBS pulses. In constant DBS (cDBS), constant stimulus intervals and amplitudes were used. Reaction and movement times during the task were measured and compared between aDBS and cDBS. The M1-γ2 activities were increased before and during movements in parkinsonian monkeys and these activities modulated the aDBS pulse interval, amplitude, and dispersion. With aDBS and cDBS, reaction and movement times were significantly decreased in comparison to DBS-OFF. The electric charge delivered was lower with aDBS than cDBS. M1-γ2 aDBS in parkinsonian monkeys resulted in clinical benefits that did not exceed those from cDBS. However, M1-γ2 aDBS achieved this magnitude of benefit for only two thirds of the charge delivered by cDBS. In conclusion, M1-γ2 aDBS is an effective therapeutic approach which requires a lower electrical charge delivery than cDBS for comparable clinical benefits.

Parkinsonism Differently Affects the Single Neuronal Activity in the Primary and Supplementary Motor Areas in Monkeys: An Investigation in Linear and Nonlinear Domains.

The changes in neuronal firing activity in the primary motor cortex (M1) and supplementary motor area (SMA) were compared in monkeys rendered parkinsonian by treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The neuronal dynamic was characterized using mathematical tools defined in different frameworks (rate, oscillations or complex patterns). Then, and for each cortical area, multivariate and discriminate analyses were further performed on these features to identify those important to differentiate between the normal and the pathological neuronal activity. Our results show a different order in the importance of the features to discriminate the pathological state in each cortical area which suggests that the M1 and the SMA exhibit dissimilarities in their neuronal alterations induced by parkinsonism. Our findings highlight the need for multiple mathematical frameworks to best characterize the pathological neuronal activity related to parkinsonism. Future translational studies are warranted to investigate the causal relationships between cortical region-specificities, dominant pathological hallmarks and symptoms.

Evaluation of Ceolus™ microcrystalline cellulose grades for the direct compression of enteric-coated pellets.

The preparation of multiparticulate tablets by direct compression of functionally coated pellets is technologically challenging. The objective was to investigate the influence of different grades of microcrystalline cellulose (Ceolus™ UF-711, PH-102, PH-200 and KG-802) as fillers on the properties of blends and tablets containing enteric pellets. Celphere™ spheres were drug-layered and then functionally coated with Eudragit(®) L 30 D-55/FS 30D dispersion. Tablets loaded with 50% pellets were prepared using pure or binary blends of microcrystalline cellulose fillers. The influence of the filler on the blend flow, segregation tendency, tablet hardness and enteric release properties were studied using a mixture design, and the optimum filler composition was determined. Rapidly disintegrating tablets, which yielded a drug release of less than 10% after 2 hours in acidic medium, could be successfully prepared. The blend composition had a significant effect on the flowability, but less on the tablet hardness which was influenced by the selection of lubricant. Blends containing celluloses with low bulk densities exhibited a reduced tendency to segregate. Pellet distribution uniformity was further improved when using Ceolus™ UF-711 blended with a high-density grade. As a conclusion, multiparticulate tablets containing enteric pellets with preserved delayed-release properties were successfully prepared using Ceolus™ microcrystalline celluloses as tableting excipients. The optimized filler blend for the direct compression of 50% enteric pellets into tablets contained Ceolus™ UF-711 as main component in combination with Ceolus™ PH-200.

Use of highly compressible Ceolus™ microcrystalline cellulose for improved dosage form properties containing a hydrophilic solid dispersion.

The development of amorphous solid dispersions containing poorly soluble drug substances has been well-documented; however, little attention has been given to the development of the finished dosage form. The objective of this study was to investigate the use of Ceolus(™) microcrystalline cellulose, a highly compressible excipient, for the production of rapidly disintegrating tablets containing a hydrophilic solid dispersion of a poorly soluble drug, indomethacin. Solid dispersions of indomethacin and Kollidon(®) VA64 were prepared by hot melt extrusion and characterized for amorphous nature. Milled dispersion particles at 500 mg/g drug loading were shown to be amorphous by differential scanning calorimetry and provided rapid dissolution in sink conditions. Physical characterization of the milled extrudate showed that the particle size of the intermediate was comparable with Ceolus(™) PH-102 and larger than the high compressibility grades of microcrystalline cellulose selected for the trial (Ceolus(™) KG-802, Ceolus(™) UF-711). Preliminary tableting trials showed that dissolution performance was significantly reduced for formulations at dispersion loadings in excess of 50%. Using a mixture design of experiments (DOE), the levels of PH-102, KG-802, UF-711, and PH-301 were optimized. Trials revealed a synergistic relationship between conventional grades (PH-102 and PH-301) and highly compressible grades (KG-802 and UF-711) leading to improved compression characteristics and more rapid dissolution rates. The formulation and resulting compressibility were also shown to have an impact on in vitro supersaturation indicating tablet formulation could impact oral bioavailability. Through the use of highly compressible microcrystalline cellulose grades such as Ceolus(™) KG-802 and UF-711, it may be possible to maximize the bioavailability benefit of amorphous solid dispersions administered as tablet dosage forms.