Chronic Ketamine Exposure Causes White Matter Microstructural Abnormalities in Adolescent Cynomolgus Monkeys

Abstract

Acute and repeated exposures to ketamine mimic aspects of positive, negative, and cognitive symptoms of schizophrenia in humans. Recent studies by our group and others have shown that chronicity of ketamine use may be a key element for establishing a more valid model of cognitive symptoms of schizophrenia. However, current understanding on the long-term consequences of ketamine exposure on brain circuits has remained incomplete, particularly with regard to microstructural changes of white matter tracts that underpin the neuropathology of schizophrenia. Thus, the present study aimed to expand on previous investigations by examining causal effects of repeated ketamine exposure on white matter integrity in a non-human primate model. Ketamine or saline (control) was administered intravenously for 3 months to male adolescent cynomolgus monkeys (n = 5/group). Diffusion tensor imaging (DTI) experiments were performed and tract-based spatial statistics (TBSS) was used for data analysis. Fractional anisotropy (FA) was quantified across the whole brain. Profoundly reduced FA on the right side of sagittal striatum, posterior thalamic radiation (PTR), retrolenticular limb of the internal capsule (RLIC) and superior longitudinal fasciculus (SLF), and on the left side of PTR, middle temporal gyrus and inferior frontal gyrus were observed in the ketamine group compared to controls. Diminished white matter integrity found in either fronto-thalamo-temporal or striato-thalamic connections with tracts including the SLF, PTR, and RLIC lends support to similar findings from DTI studies on schizophrenia in humans. This study suggests that chronic ketamine exposure is a useful pharmacological paradigm that might provide translational insights into the pathophysiology and treatment of schizophrenia.

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

“…Additionally, studies in nonhuman primates have reported that repeated daily ketamine administration (1 mg/kg per day, i.v. ): 1) reduced white matter integrity in fronto-thalamo-temporal connections as assessed by diffusion tensor imaging following a 3-month treatment (Li et al, 2017), and 2) increased cell death in the prefrontal cortex as assessed by terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining of brain sections obtained from animals treated for 6 months (Sun et al, 2014).…”

Disruptions in White Matter Maturation and Mediation of Cognitive Development in Youths on the Psychosis Spectrum

“…To our knowledge, there are no studies that focus specifically on the RLIC in relation to psychosis, though there is previous evidence for an association of reduced RLIC FA with psychosis. Nonhuman adolescent primates receiving daily exposure to ketamine (an N-methyl-Daspartate antagonist used to mimic psychotic symptoms) showed reduced FA in multiple tracts, including the RLIC and SLF (87). Furthermore, a longitudinal study found that patients (20-40 years of age) with SZ showed an attenuated increase in RLIC FA across a 3year follow-up relative to control subjects (88).…”

Use of Ketamine to Treat Depressive Symptoms in Schizoaffective Disorder

“…Thus, ketamine may be able to positively effect the abnormal speech area connections. Additionally, chronic ketamine exposure damages white matter in the brains of cynomolgus monkeys [5]. If this observation translates to human physiology as well, it is possible that controlled ketamine exposure may balance out the increase in white matter brought about by auditory hallucinations.…”