Decoding effects of psychoactive drugs in a high-dimensional space of eye movements in monkeys.

Oculomotor behavior has been shown to be correlated with mental disorders in clinics, making it promising for disease diagnosis. Here we developed a thorough oculomotor test toolkit, involving saccade, smooth pursuit, and fixation, allowing the examination of multiple oculomotor parameters in monkey models induced by psychoactive drugs. Eye movements were recorded after daily injections of phencyclidine (PCP) (3.0 mg/kg), ketamine (0.8 mg/kg) or controlled saline in two macaque monkeys. Both drugs led to robust reduction in accuracy and increment in reaction time during high cognitive-demanding tasks. Saccades, smooth pursuit, and fixation stability were also significantly impaired. During fixation, the involuntary microsaccades exhibited increased amplitudes and were biased toward the lower visual field. Pupillary response was reduced during cognitive tasks. Both drugs also increased sensitivity to auditory cues as reflected in auditory evoked potentials (AEPs). Thus, our animal model induced by psychoactive drugs produced largely similar abnormalities to that in patients with schizophrenia. Importantly, a classifier based on dimension reduction and machine learning could reliably identify altered states induced by different drugs (PCP, ketamine and saline, accuracy = 93%). The high performance of the classifier was reserved even when data from one monkey were used for training and testing the other subject (averaged classification accuracy = 90%). Thus, despite heterogeneity in baseline oculomotor behavior between the two monkeys, our model allows data transferability across individuals, which could be beneficial for future evaluation of pharmaceutical or physical therapy validity.

Oculomotor Performances Are Associated With Motor and Non-motor Symptoms in Parkinson's Disease.

Background: Parkinson's disease (PD) patients exhibit deficits in oculomotor behavior, yet the results are inconsistent across studies. In addition, how these results are associated with clinical symptoms is unclear, especially in China. Methods: We designed a case-control study in China including 37 PD patients and 39 controls. Clinical manifestations in PD patients were recorded. Oculomotor performance was measured by a video-based eye tracker system. Results: We found that six oculomotor parameters, including fixation stability, saccadic latency, smooth pursuit gain, saccade frequency, viewing range, and saccade frequency during free-viewing context, were significantly different in PD patients and control group. Combining application of these six parameters could improve diagnostic accuracy to over 90%. Moreover, pursuit gain was significantly associated with PD duration, UPDRS III, in PD patients. Saccade latency was significantly associated with PD duration, Berg balance score, RBD score, and Total LEDD in PD patients. Conclusions: PD patients commonly exhibit oculomotor deficits in multiple behavioral contexts, which are associated with both motor and non-motor symptoms. Oculomotor test may provide a valuable tool for the clinical assessment of PD.

Age-dependent alterations in the presynaptic active zone in a Drosophila model of Alzheimer's disease.

The accumulation of beta amyloid (Aß) can cause synaptic impairments, but the characteristics and mechanisms of the synaptic impairment induced by the accumulation of Aß in Alzheimer's disease (AD) remain unclear. In identified single neurons in a newly developed Drosophila AD model, in which Aß accumulates intraneuronally, we found an age-dependent reduction in the synaptic vesicle release probability that was associated with a decrease in the density of presynaptic calcium channel clusters and an increase in the presynaptic and postsynaptic contact length. Moreover, these alterations occurred in the absence of presynaptic bouton loss. In addition, we found that Aß expression also produced an age-dependent decrease in the amount of Bruchpilot (Brp), which plays an important role in controlling Ca(2+) channel clustering and synaptic vesicle release in the presynaptic active zone. Our study indicates that the chronic accumulation of intraneuronal Aß can induce functional and structural changes in the presynaptic active zone prior to a loss of presynaptic buttons in the same neuron.

Expression of beta-amyloid induced age-dependent presynaptic and axonal changes in Drosophila.

Alzheimer's disease (AD) is attributable to synapse dysfunction and loss, but the nature and progression of the presynaptic structural and functional changes in AD are essentially unknown. We expressed wild-type or arctic form of beta amyloid(1-42) (Abeta) in a small group of neurons in the adult fly and performed extensive time course analysis of the function and structure of both axon and presynaptic terminals at the identified single-neuron level. Abeta accumulated intracellularly and induced a range of age-dependent changes, including depletion of presynaptic mitochondria, slowdown of bi-directional transports of axonal mitochondria, decreased synaptic vesicles, increased large vacuoles, and elevated synaptic fatigue. These structural and functional synaptic changes correlated with age-dependent deficit in motor behavior. All these alterations were accelerated in flies expressing the arctic form of Abeta. The depletion of presynaptic mitochondria was the earliest detected phenotype and was not caused by the change in axonal transport of mitochondria. Moreover, axonal mitochondria exhibited a dramatic reduction in number but a significant increase in size in aged Abeta-expressing flies, indicating a global depletion of mitochondria in the neuron and an impairment of mitochondria fission. These results suggest that Abeta accumulation depletes presynaptic and axonal mitochondria, leading to other presynaptic deficits.