Gary S. Linn

Phencyclidine (PCP)-induced deficits of prepulse inhibition in monkeys.

Prepulse inhibition (PPI) of the acoustic startle reflex is a measure of sensorimotor gating which occurs in both rodents and humans. PPI is deficient in severe neuropsychiatric disorders such as schizophrenia. We investigated PPI in 10 adult monkeys (Cebus apella). Stimuli were 115 dB white noise startle pulses, either alone or preceded by 120 ms with a prepulse of either 8 or 16 dB above the 70 dB background noise. Experiments included a pretreatment baseline session and a session following treatment with either phencyclidine (PCP, 0.12 mg/kg, i.m.) or saline. Comparison of peak ampli- tudes indicated a significant intensity-dependent decrease in startle response that was similar to that observed in humans under similar experimental conditions. PCP treatment significantly disrupted PPI, but did not reduce responses to startle pulses alone. These results provide the first demonstration of PPI in monkeys. The ability of PCP to induce schizophrenia-like deficits in PPI suggests that PPI in nonhuman primates may provide an important animal model for the development of novel anti-schizophrenia medications.

Spatiotemporal structure of intracranial electric fields induced by transcranial electric stimulation in humans and nonhuman primates.

Transcranial electric stimulation (TES) is an emerging technique, developed to non-invasively modulate brain function. However, the spatiotemporal distribution of the intracranial electric fields induced by TES remains poorly understood. In particular, it is unclear how much current actually reaches the brain, and how it distributes across the brain. Lack of this basic information precludes a firm mechanistic understanding of TES effects. In this study we directly measure the spatial and temporal characteristics of the electric field generated by TES using stereotactic EEG (s-EEG) electrode arrays implanted in cebus monkeys and surgical epilepsy patients. We found a small frequency dependent decrease (10%) in magnitudes of TES induced potentials and negligible phase shifts over space. Electric field strengths were strongest in superficial brain regions with maximum values of about 0.5 mV/mm. Our results provide crucial information of the underlying biophysics in TES applications in humans and the optimization and design of TES stimulation protocols. In addition, our findings have broad implications concerning electric field propagation in non-invasive recording techniques such as EEG/MEG.

Behavioral effects of chronic phencyclidine in monkeys.

Phencyclidine (PCP) and other NMDA receptor antagonists such as ketamine induce psychotic symptoms that are difficult to reverse with current medications and which closely resemble those of schizophrenia. This study investigated the behavioral effects of continuous PCP administration in six socially-housed Cebus apella monkeys. Chronic treatment was associated with a sustained decrease in stereotyped locomotion (pacing) and a sustained increase in scanning behavior. Treatment was also associated with a modest decrease in self- and environment-directed behavior and goal-directed locomotion and an increase in affiliative behavior at lower doses. Four animals had one or more episodes of extreme motoric and physiological responses precipitated by stressful events. The results indicate that behavioral effects of chronic PCP in primates differ from those seen following acute treatments and represent an appropriate model system for new antipsychotic drug development.

Effect of extended depot fluphenazine treatment and withdrawal on social and other behaviors ofCebus apella monkeys

To examine whether or not prolonged exposure to a depot neuroleptic has either residual or “tardive pathological” effects onnormal behavior, 38Cebus apella monkeys were observed daily for 108 weeks. The issue of stress influencing such effects was also addressed. During weeks 25–48 half of the monkeys received 0.22 mg/kg fluphenazine decanoate, IM, every 3 weeks, with the dose increased to 0.33 mg/kg during weeks 49–72. Behavioral measures were combined to form composite behavioral variables which quantify four major aspects of behavior: self- and environment-directed behavior, affiliation, aggression, and normal locomotor activity. Mean plasma fluphenazine levels at 48 h post-injection were 0.13 (±0.03) ng/ml for injections 3–8 and 0.24 (±0.07) ng/ml for injections 11–16. The pre-study null hypothesis that the four major aspects of behavior would not be adversely affected by this treatment during the drug-discontinuation phase of the study (weeks 73–108) wasnot statistically negated. There were highly significant decreases in self-and environment-directed behaviors and affiliation during the treatment periods, implying that treatment may contribute to the negative symptoms of treated schizophrenics. Stress reduced the above effects. Aggression showed some increase during early drug discontinuation, accentuated by stress. Recovery of normal (baseline) behavioral scores began by week 7 after the last treatment. Mild (bucco-lingual) tardive dyskinesias persisted in 30% of the animals for a prolonged time.

Limitations of ex vivo measurements for in vivo neuroscience

Significance Understanding the physiology of noninvasive brain stimulation requires precise knowledge of biophysical properties of brain tissue (e.g., conductivities). Numerous researchers have tried to measure these properties using in vitro, in vivo, and ex vivo preparations in nonhuman animals or human tissue, though findings have tended to vary across studies. We measured electric fields in the nonhuman primate brain during transcranial electric stimulation both in vivo and ex vivo. We found large changes in electric fields between in vivo and ex vivo measurements that increased with postmortem time, along with a significant effect of body temperature on electric field strength. Our findings underscore the necessity of nonhuman animal models for systematic study of brain stimulation effects under biophysically realistic conditions. A long history of postmortem studies has provided significant insight into human brain structure and organization. Cadavers have also proven instrumental for the measurement of artifacts and nonneural effects in functional imaging, and more recently, the study of biophysical properties critical to brain stimulation. However, death produces significant changes in the biophysical properties of brain tissues, making an ex vivo to in vivo comparison complex, and even questionable. This study directly compares biophysical properties of electric fields arising from transcranial electric stimulation (TES) in a nonhuman primate brain pre- and postmortem. We show that pre- vs. postmortem, TES-induced intracranial electric fields differ significantly in both strength and frequency response dynamics, even while controlling for confounding factors such as body temperature. Our results clearly indicate that ex vivo cadaver and in vivo measurements are not easily equitable. In vivo examinations remain essential to establishing an adequate understanding of even basic biophysical phenomena in vivo.

Delineating the Macroscale Areal Organization of the Macaque Cortex In Vivo.

Complementing long-standing traditions centered on histology, fMRI approaches are rapidly maturing in delineating brain areal organization at the macroscale. The non-human primate (NHP) provides the opportunity to overcome critical barriers in translational research. Here, we establish the data requirements for achieving reproducible and internally valid parcellations in individuals. We demonstrate that functional boundaries serve as a functional fingerprint of the individual animals and can be achieved under anesthesia or awake conditions (rest, naturalistic viewing), though differences between awake and anesthetized states precluded the detection of individual differences across states. Comparison of awake and anesthetized states suggested a more nuanced picture of changes in connectivity for higher-order association areas, as well as visual and motor cortex. These results establish feasibility and data requirements for the generation of reproducible individual-specific parcellations in NHPs, provide insights into the impact of scan state, and motivate efforts toward harmonizing protocols.

Effects of dopamine agonists on Cebus apella monkeys with previous long-term exposure to fluphenazine

Sixty-one weeks after 48 weeks of treatment with fluphenazine decanoate or placebo, 37 socially living Cebus apella monkeys were evaluated for differences in dopaminergic sensitivity by exposure to 0.75 mg/kg, i.m. of amphetamine (AMPH) (indirect agonist) and apomorphine (APOM) (direct agonist). The fluphenazine-treated animals differed (p < or = 0.05) from control animals on some hourly measures of composite behavioral variables (CBVs). Animals exposed to fluphenazine showed a greater decrease in the aggressiveness CBV and a smaller decrease in self- and environment-directed behaviors than placebo animals. CBVs for normal locomotion and directs affiliation showed no significant differences. The fluphenazine-treated group showed greater agonist induction of stereotypic behavior (p < or = 0.01), and larger decreases in prolactin response to AMPH (p < or = 0.05). Our findings indicate that following extended treatment with an antipsychotic there is increased sensitivity to dopamine, as evidenced by stereotypies and possibly hypophyseal responsiveness.

Electric field dynamics in the brain during multi-electrode transcranial electric stimulation

Neural oscillations play a crucial role in communication between remote brain areas. Transcranial electric stimulation with alternating currents (TACS) can manipulate these brain oscillations in a non-invasive manner. Of particular interest, TACS protocols using multiple electrodes with phase shifted stimulation currents were developed to alter the connectivity between two or more brain regions. Typically, an increase in coordination between two sites is assumed when they experience an in-phase stimulation and a disorganization through an anti-phase stimulation. However, the underlying biophysics of multi-electrode TACS has not been studied in detail, thus limiting our ability to develop a mechanistic understanding. Here, we leverage direct invasive recordings from two non-human primates during multi-electrode TACS to show that the electric field magnitude and phase depend on the phase of the stimulation currents in a non-linear manner. Further, we report a novel phenomenon of a “traveling wave” stimulation where the location of the electric field maximum changes over the stimulation cycle. Our results provide a basis for a mechanistic understanding of multi-electrode TACS, necessitating the reevaluation of previously published studies, and enable future developments of novel stimulation protocols.