Abnormalities in White Matter Microstructure Associated with Chronic Ketamine Use

Abstract

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has been found to induce schizophrenia-type symptoms in humans and is a potent and fast-acting antidepressant. It is also a relatively widespread drug of abuse, particularly in China and the UK. Acute administration has been well characterized, but the effect of extended periods of ketamine use-on brain structure in humansremains poorly understood. We measured indices of white matter microstructural integrity and connectivity in the brain of 16 ketamine users and 16 poly-drug-using controls, and we used probabilistic tractography to quantify changes in corticosubcortical connectivity associated with ketamine use. We found a reduction in the axial diffusivity profile of white matter in a right hemisphere network of white matter regions in ketamine users compared with controls. Within the ketamine-user group, we found a significant positive association between the connectivity profile between the caudate nucleus and the lateral prefrontal cortex and dissociative experiences. These findings suggest that chronic ketamine use may be associated with widespread disruption of white matter integrity, and white matter pathways between subcortical and prefrontal cortical areas may in part predict individual differences in dissociative experiences due to ketamine use.

Efficacy of ketamine in the rapid treatment of major depressive disorder: a meta-analysis of randomized, double-blind, placebo-controlled studies

“…A previous study reported that ketamine was associated with impairment of working, episodic, and procedural memory function,43 and long-term ketamine abuse could result in persistent neurocognitive impairments44 and even potential harmful brain changes 45. Although our study indicated that ketamine might have rapid antidepressant effects in patients with TRD, its impact on the neurocognitive function of patients with TRD has been assessed by only few studies to date.…”

Cognitive dysfunction in major depression and Alzheimer's disease is associated with hippocampus–prefrontal cortex dysconnectivity

“…Although this suggests that impaired connectivity can be rescued, it is critical to understand ketamine’s impact on white matter. Efforts should be aimed at distinguishing between acute and chronic effects, as chronic ketamine usage has been shown to disrupt connectivity between the caudate and PFC 103. Focusing attention on understanding the molecular substrates that influence white-matter integrity would be an important research avenue.…”

Approaching a network connectivity-driven classification of the psychosis continuum: a selective review and suggestions for future research

“…With regard to the FP pathway, a recent study suggests that psychotic patients have glutamate-related dysregulation of the brain network supporting cognitive control (Falkenberg et al, 2014 ). The NMDAR antagonist ketamine induces psychotic-like experiences that are highly reminiscent of those observed in schizophrenia (Krystal et al, 1994 , 2005 ; Schmidt et al, 2012 ), so it is intriguing that this also reduces diffusivity in the superior longitudinal fasciculus (Edward Roberts et al, 2014 ). It has further been demonstrated that ketamine reduced the negative correlation between the FP system and the default network in healthy volunteers, while the degree of this disruption predicted task performance (Anticevic et al, 2012 ).…”