Ketamine induced converged synchronous gamma oscillations in the cortico-basal ganglia network of nonhuman primates

Abstract

-methyl-d-aspartate (NMDA) antagonists are widely used in anesthesia, pain management, and schizophrenia animal model studies, and recently as potential antidepressants. However, the mechanisms underlying their anesthetic, psychotic, cognitive, and emotional effects are still elusive. The basal ganglia (BG) integrate input from different cortical domains through their dopamine-modulated connections to achieve optimal behavior control. NMDA antagonists have been shown to induce gamma oscillations in human EEG recordings and in rodent cortical and BG networks. However, network relations and implications to the primate brain are still unclear. We recorded local field potentials (LFPs) simultaneously from the primary motor cortex (M1) and the external globus pallidus (GPe) of four vervet monkeys (26 sessions, 97 and 76 cortical and pallidal LFPs, respectively) before and after administration of ketamine (NMDA antagonist, 10 mg/kg im). Ketamine induced robust, spontaneous gamma (30-50 Hz) oscillations in M1 and GPe. These oscillations were initially modulated by ultraslow oscillations (~0.3 Hz) and were highly synchronized within and between M1 and the GPe (mean coherence magnitude = 0.76, 0.88, and 0.41 for M1-M1, GPe-GPe, and M1-GPe pairs). Phase differences were distributed evenly around zero with broad and very narrow distribution for the M1-M1 and GPe-GPe pairs (-3.5 ± 31.8° and -0.4 ± 6.0°), respectively. The distribution of M1-GPe phase shift was skewed to the left with a mean of -18.4 ± 20.9°. The increased gamma coherence between M1 and GPe, two central stages in the cortico-BG loops, suggests a global abnormal network phenomenon with a unique spectral signature, which is enabled by the BG funneling architecture. This study is the first to show spontaneous gamma oscillations under NMDA antagonist in nonhuman primates. These oscillations appear in synchrony in the cortex and the basal ganglia. Phase analysis refutes the confounding effects of volume conduction and supports the funneling and amplifying architecture of the cortico-basal ganglia loops. These results suggest an abnormal network phenomenon with a unique spectral signature that could account for pathological mental and neurological states.

In vivo electrophysiological recordings of the effects of antidepressant drugs

“…So at this point, little is known about single unit firing in the rapidly acting antidepressant ketamine, or the related NMDAR antagonists dizocilpine (MK-801) and phencyclidine (PCP). One finding that has been replicated a number of times in these studies, including for ketamine in vervet monkeys (Slovik et al 2017 ) and macaques (Skoblenick et al 2016 ), is that acute systemic administration of these three drugs, and in some cases infusion of them into local brain regions, tends to enhance gamma and high frequency oscillations (HFO) in a number of cortical and subcortical structures (Hakami et al 2009 ; Hunt et al 2008 , 2009 , 2010 ; Kealy et al 2017 ; Kjaerby et al 2017 ; Lee et al 2017 ; Matulewicz et al 2010 ; Nagy et al 2016 ; Nicolás et al 2011 ; Olszewski et al 2013 ; Wood et al 2012 ; Hunt et al 2006 ; Sullivan et al 2015 ; Maheshwari et al 2016 ). Of note, Hunt et al ( 2015 ) found that acute MK-801 not only increased the power of nucleus accumbens HFO but also produced a small increase in frequency, whereas the 5-HT2A antagonist clozapine and 5-HT1A agonist 8-OH-DPAT each counteracted this increase in frequency, suggesting functional opposition between these two 5-HT receptor subtypes in this effect (Hunt et al 2015 ).…”

Pharmaco‐electroencephalographic responses in the rat differ between active and inactive locomotor states

“…In our study, ketamine and DOI produced beta activity suppression occurring specifically in the inactive state and the suppression was also observable in the total data. Ketamine‐induced suppression of beta power appears stable across species as decreases have also been found in LFPs from mice (Lazarewicz et al., ), vervet monkeys (Slovik et al., ) and in human EEG (Knott et al., ) and MEG recordings (Muthukumaraswamy et al., ; Rivolta et al., ). Only one human study did not find any effect of ketamine on current densities in the beta band (de La Salle et al., ).…”

Dopaminergic neuromodulation of high gamma stimulus phase‐locking in gerbil primary auditory cortex mediated by D1/D5‐receptors

“…However, as there was no antagonistic pattern of change for the induced background power after consecutive administration of SKF‐38393 and SCH‐23390, it cannot be ruled out that the observed broadband and low‐frequency effects might be due or at least be partially confounded by temporal changes related to anesthesia. Ketamine used for anesthesia in our study has been shown to alter neuronal oscillations in for instance lower frequencies (Blain‐Moraes et al ., ) or higher frequency ranges (Lazarewicz et al ., ; Slovik et al ., ). Ketamine anesthesia has been shown to reduce NMDA‐mediated synaptic input to inhibitory interneurons, as well as to pyramidal neurons, and by this contribute to the observed effects.…”