Frontal Responses During Learning Predict Vulnerability to the Psychotogenic Effects of Ketamine

105

There is now considerable evidence to support the hypothesis that psychotic symptoms are the result of abnormal salience attribution, and that the attribution of salience is largely mediated through the prefrontal cortex, the striatum, and the hippocampus. Although these areas show differential activation under the influence of delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), the two major derivatives of cannabis sativa, little is known about the effects of these cannabinoids on the functional connectivity between these regions. We investigated this in healthy occasional cannabis users by employing event-related functional magnetic resonance imaging (fMRI) following oral administration of delta-9-THC, CBD, or a placebo capsule. Employing a seed cluster-based functional connectivity analysis that involved using the average time series from each seed cluster for a whole-brain correlational analysis, we investigated the effect of drug condition on functional connectivity between the seed clusters and the rest of the brain during an oddball salience processing task. Relative to the placebo condition, delta-9-THC and CBD had opposite effects on the functional connectivity between the dorsal striatum, the prefrontal cortex, and the hippocampus. Delta-9-THC reduced fronto-striatal connectivity, which was related to its effect on task performance, whereas this connection was enhanced by CBD. Conversely, mediotemporal-prefrontal connectivity was enhanced by delta-9-THC and reduced by CBD. Our results suggest that the functional integration of brain regions involved in salience processing is differentially modulated by single doses of delta-9-THC and CBD and that this relates to the processing of salient stimuli.

Section: Discussionsupporting

confidence: 76%

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

Bhattacharyya

Falkenberg

Martín‐Santos

et al. 2014

105

“…Here, we found that the MMN slope under placebo showed a negative correlation with the subsequent ketamine-induced extent of cognitive impairments across subjects; in contrast, no comparable relationship was found for psilocybin. Although this result is in accordance with Umbricht's MMN study (Umbricht et al, 2002), it may not appear to be fully consistent with the results by Corlett et al (2006), who found that frontal PE signals under placebo, measured during an associative learning task with fMRI, exhibited a positive correlation with the severity of positive symptoms (delusions, perceptual aberrations) under ketamine. However, the results from the two studies are not directly comparable owing to a number of major methodological differences, including different symptom rating scales, different ketamine dosage and application regimens, different measurement techniques (fMRI vs EEG), and, perhaps most importantly, fundamentally different cognitive paradigms.…”

Section: S-ketamine-induced Cognitive Impairmentscontrasting

confidence: 64%

“…This approach is inspired by the general notion that the development of psychiatric disease may result from the interplay between the (genetically determined) susceptibility of an individual and the expose to environmental stressors (Brown, 2011), and follows previous studies, which examined whether physiological markers can predict the individual degree of psychotic symptoms in drug-induced psychosis and schizophrenia (Corlett et al, 2006;Honey et al, 2008;Krystal et al, 2003;Umbricht et al, 2002). Here, we found that the MMN slope under placebo showed a negative correlation with the subsequent ketamine-induced extent of cognitive impairments across subjects; in contrast, no comparable relationship was found for psilocybin.…”

Section: S-ketamine-induced Cognitive Impairmentsmentioning

confidence: 99%

“…This correlation was significant over frontal electrodes, suggesting that the integrity of PFC is crucial for PE processing in MMN. Another study using a different modality (fMRI) and different paradigm (an associative learning task) suggested that this role of the PFC for PE processing may generalize, reporting that ketamine disrupted PE-dependent activity in the right PFC of healthy volunteers (Corlett et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mismatch Negativity Encoding of Prediction Errors Predicts S-ketamine-Induced Cognitive Impairments

Schmidt

Bachmann

Kometer

et al. 2011

Psychotomimetics like the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine and the 5-hydroxytryptamine2A receptor (5-HT 2A R) agonist psilocybin induce psychotic symptoms in healthy volunteers that resemble those of schizophrenia. Recent theories of psychosis posit that aberrant encoding of prediction errors (PE) may underlie the expression of psychotic symptoms. This study used a roving mismatch negativity (MMN) paradigm to investigate whether the encoding of PE is affected by pharmacological manipulation of NMDAR or 5-HT 2A R, and whether the encoding of PE under placebo can be used to predict drug-induced symptoms. Using a doubleblind within-subject placebo-controlled design, S-ketamine and psilocybin, respectively, were administrated to two groups of healthy subjects. Psychological alterations were assessed using a revised version of the Altered States of Consciousness (ASC-R) questionnaire. As an index of PE, we computed changes in MMN amplitudes as a function of the number of preceding standards (MMN memory trace effect) during a roving paradigm. S-ketamine, but not psilocybin, disrupted PE processing as expressed by a frontally disrupted MMN memory trace effect. Although both drugs produced positive-like symptoms, the extent of PE processing under placebo only correlated significantly with the severity of cognitive impairments induced by S-ketamine. Our results suggest that the NMDAR, but not the 5-HT 2A R system, is implicated in PE processing during the MMN paradigm, and that aberrant PE signaling may contribute to the formation of cognitive impairments. The assessment of the MMN memory trace in schizophrenia may allow detecting early phases of the illness and might also serve to assess the efficacy of novel pharmacological treatments, in particular of cognitive impairments.

“…Acute administration of ketamine in healthy volunteers impairs performance on memory and cognitive tasks and also induces psychotic symptoms such as delusions and dissociative sensations (Krystal et al, 1994;Morgan et al, 2004a). Neuroimaging studies have reported that acute ketamine administration is associated with taskrelated reductions in prefrontal cortical activation, as measured by blood oxygenation level-dependent (BOLD) response (Corlett et al, 2006;Corlett et al, 2007). Frequent ketamine use has been found to be associated with persistent working memory and executive function impairment and psychotic-like symptoms (Morgan et al, 2004b(Morgan et al, , 2010.…”

Section: Introductionmentioning

confidence: 99%

Abnormalities in White Matter Microstructure Associated with Chronic Ketamine Use

Roberts

Curran

Friston

et al. 2013

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.