Objectively measuring effects of electro-acupuncture in parkinsonian rhesus monkeys.

Acupuncture has increasingly been used as an alternative therapy for treatment of Parkinson's disease (PD). However, the efficacy of acupunture for PD still remains unclear. The present study was designed to objectively and safely monitor anti-parkinsonian effects of electroacupuncture (EA) and brain activity in nonhuman primates modeling human PD. Six middle-aged rhesus monkeys were extensively studied by a computerized behavioral testing battery and by pharmacological MRI (phMRI) scans with specific dopaminergic drug stimulations. All animals were evaluated for behavior and phMRI responses under normal, parkinsonian, parkinsonian with EA treatment and parkinsonian after EA treatment conditions. Stable parkinsonian features were observed in all animals prior to entering the EA study and positive responses to levodopa (L-dopa) challenge were also seen in all animals. The results demonstrated that chronic EA treatments could significantly improve the movement speed and the fine motor performance time during the period of EA treatments, and the effectiveness of EA could be detected even 3 months after the EA treatment. The phMRI data revealed that chronic EA treatments could alter neuronal activity in the striatum, primary motor cortex (M1), cingulate gyrus and global pallidus externa (GPe) in the ipsilateral hemisphere to MPTP lesions. As seen in the changes of parkinsonian features, the residual effects of phMRI responses to apomorphine (APO) challenge could also be found in the aforementioned areas. The results strongly suggest that anti-parkinsonian effects of EA can be objectively assessed, and the method used in the present study could be translated into the human clinic with some minor modifications.

Decreased mitochondrial bioenergetics and calcium buffering capacity in the basal ganglia correlates with motor deficits in a nonhuman primate model of aging.

Altered mitochondrial function in the basal ganglia has been hypothesized to underlie cellular senescence and promote age-related motor decline. We tested this hypothesis in a nonhuman primate model of human aging. Six young (6-8 years old) and 6 aged (20-25 years old) female Rhesus monkeys (Macaca mulatta) were behaviorally characterized from standardized video records. Additionally, we measured mitochondrial bioenergetics along with calcium buffering capacity in the substantia nigra and putamen (PUT) from both age groups. Our results demonstrate that the aged animals had significantly reduced locomotor activity and movement speed compared with younger animals. Moreover, aged monkeys had significantly reduced ATP synthesis capacity (in substantia nigra and PUT), reduced pyruvate dehydrogenase activity (in PUT), and reduced calcium buffering capacity (in PUT) compared with younger animals. Furthermore, this age-related decline in mitochondrial function in the basal ganglia correlated with decline in motor function. Overall, our results suggest that drug therapies designed to enhance altered mitochondrial function may help improve motor deficits in the elderly.

Improved methods for electroacupuncture and electromyographic recordings in normal and parkinsonian rhesus monkeys.

Although acupuncture has been widely and routinely used in healthcare in the USA, its use has been based more on empirical observation than on scientific knowledge. Therefore, there is a great need for better understanding the underlying mechanism(s) of action. A great body of evidence supports that nonhuman primates are a candidate for studying human diseases. However, the use of nonhuman primates in neurophysiological, neuroimaging and neurochemical studies is extremely challenging, especially under fully conscious, alert conditions. In the present study, we developed a protocol for safely performing acupuncture, electroacupuncture (EA) and electromyography (EMG) in both normal nonhuman primates and animals with parkinsonian-like symptoms. Four normal and four hemiparkinsonian middle-aged rhesus monkeys were extensively trained, behaviorally monitored, and received both EA and EMG for several months. The results demonstrated that (1) all rhesus monkeys used in the study could be trained for procedures including EA and EMG; (2) all animals tolerated the procedures involving needle/electrode insertion; (3) EA procedures used in the study did not adversely alter the animal's locomotor activities; rather, MPTP-treated animals showed a significant improvement in movement speed; and (4) EMG detected significant differences in muscle activity between the arms with and without MPTP-induced rigidity. Our results support that rhesus monkeys can be used as an experimental animal model to study EA and that EMG has the potential to be used to objectively assess the effects of antiparkinsonian therapies. The results also indicate that animals, especially those with parkinsonian-like symptoms, could benefit from long-term EA stimulations.

Amperometric measures of age-related changes in glutamate regulation in the cortex of rhesus monkeys.

l-glutamate (glutamate) is the principal excitatory neurotransmitter of the central nervous system and is involved in altered neural function during aging and in neurodegenerative diseases. Relatively little is known about the mechanisms of glutamate signaling in the primate brain, in part, because there is an absence of a method capable of rapidly measuring glutamate in either a non-clinical or a clinical setting. We have addressed this paucity of information by measuring extracellular glutamate at 1 Hz in the pre-motor and motor cortices of young, middle-aged, and aged monkeys using a minimally invasive amperometric recording method. In the motor cortex, mean resting glutamate levels were five times higher in the aged group compared to the young group while the pre-motor cortex showed an increasing trend in resting glutamate levels that was not statistically significant. In addition, we measured rapid, phasic glutamate release after local pressure-ejection of nanoliter volumes of either isotonic 70 mM potassium (to stimulate glutamate release) or 1 mM glutamate (to study glutamate uptake) into the pre-motor and motor cortex. In the pre-motor cortex, we measured reproducible glutamate uptake signals that had a significantly decreased (47%) rate of glutamate uptake in aged animals compared to young animals. However, following a 70 mM potassium delivery, we did not observe any consistent changes in evoked release between young versus aged animals. Using these non-clinical microelectrodes to measure glutamate signaling in the brain, our results support the hypothesis that the glutamatergic system undergoes reorganization with aging of the central nervous system.