Limitations of ex vivo measurements for in vivo neuroscience.

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.

Behavioral effects of orally administered glycine in socially housed monkeys chronically treated with phencyclidine.

RATIONALE: Schizophrenia is a major mental disorder. Dissociative anesthetics such as phencyclidine (PCP) produce a syndrome in humans that is clinically indistinguishable from schizophrenia by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. NMDA receptors in brain are modulated by the amino acid glycine (GLY), which reverses neurochemical and behavioral effects of PCP in rodents. The present study investigates GLY effects on PCP-induced behavior in primates. OBJECTIVES: In primates, PCP induces characteristic behavioral symptoms that can be used to model positive and negative symptoms of schizophrenia. This study investigated the effects of GLY treatment in ten socially housed monkeys receiving chronically infused PCP. METHODS: Ten monkeys received escalating then stable doses of continuously infused PCP through a series of subcutaneously implanted osmotic minipumps. During a segment of the highest PCP dose period, monkeys were concurrently treated with glycine (2 g kg(-1) day(-1) bid p.o.). Behavioral observations were recorded during baseline and treatment periods. RESULTS: Chronic PCP treatment was associated with a progressive decrease in stereotyped pacing and a progressive increase in scanning behavior. Eight of ten animals had one or more episodes of extreme motoric and physiological responses precipitated by stressful events. GLY treatment significantly reversed the effects of PCP on stereotyped pacing but had no effect on scanning. CONCLUSIONS: The results support GLY treatment as beneficial for negative symptoms of schizophrenia. Although further validation is needed, the results also indicate that chronic PCP in primates may be an appropriate model system for development of drugs targeting positive and negative symptoms of schizophrenia.

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.

Reversal of phencyclidine-induced prepulse inhibition deficits by clozapine in monkeys.

RATIONALE: Prepulse inhibition (PPI) of the acoustic startle reflex is a measure of sensorimotor gating, which occurs across species and is deficient in severe neuropsychiatric disorders such as schizophrenia. In monkeys, as in rodents, phencyclidine (PCP) induces schizophrenia-like deficits in PPI. In rodents, in general, typical antipsychotics (e.g. haloperidol) reverse PPI deficits induced by dopamine (DA) agonists (e.g. apomorphine), but not those induced by N-methyl- d-aspartate (NMDA) receptor antagonists [e.g. phencyclidine (PCP)], whereas atypical antipsychotics (e.g. clozapine) reverse PPI deficits induced by DA agonists and NMDA antagonists. However, some discrepancies exist with some compounds and strains of rodents. OBJECTIVES: This study investigated whether a typical (haloperidol, 0.035 mg/kg) and an atypical (clozapine, 2.5 mg/kg) antipsychotic could be distinguished in their ability to reverse PCP-induced deficits in PPI in eight monkeys ( Cebus apella). METHODS: First, haloperidol dose was determined by its ability to attenuate apomorphine-induced deficits in PPI. Then, haloperidol and clozapine were tested in eight monkeys with PCP-induced deficits of PPI. Experimental parameters were similar to standard human PPI procedures, with 115 dB white noise startle pulses, either alone or preceded by 120 ms with a prepulse 16 dB above the 70 dB background noise. RESULTS: Clozapine reversed PCP-induced PPI deficits. In contrast, haloperidol did not significantly attenuate PCP-induced PPI deficits even at doses that significantly attenuated apomorphine effects. CONCLUSIONS: In this primate model, clozapine was distinguishable from haloperidol by its ability to attenuate PCP-induced deficits in PPI. The results provide further evidence that PPI in nonhuman primates may provide an important animal model for the development of novel anti-schizophrenia medications.