Visualising the Effects of Ketamine

What is ketamine?
Ketamine is an anaesthetic which was first developed by the drug company Parke-Davis in 1962. It is typically considered a ‘dissociative’ anaesthetic due to the unusual effects it can produce, which include out-of-body experiences. Recent years have also seen significant growth in its use within the party scene, where it is commonly referred to as ‘Special K’. However, as it has a safety profile superior to that of many other anaesthetics, ketamine is still widely used by clinicians for emergency, paediatric and veterinary anaesthesia (Jansen, 2001; Perry et al., 2007).

Ketamine as a Pharmacological Model of Mental Illness
The administration of an anaesthetic dose of ketamine can elicit ‘hallucinations, vivid dreams and floating sensations’ (Reich & Silvay, 1989), p.188). At lower doses, ketamine has been shown to alter the intensity of perceived colours and sounds, to disturb the subjective flow of time and to imbue common place occurrences or objects with a sense of personal importance. Ketamine may also cause individuals to become emotionally detached and withdrawn, and more recent findings indicate it has a detrimental effect on aspects of cognitive performance (Coull et al., 2011; Krystal et al., 1994; Pomarol-Clotet et al., 2006) .

This particular cluster of symptoms which echoes the pattern of symptoms seen in schizophrenia (e.g. hallucinations and delusions, blunted affect and cognitive deficits), has led to the extensive study of ketamine as a pharmacological model of this mental illness. Recent evidence that ketamine may be beneficial in the treatment of depression has also raised considerable interest, as acute administration of ketamine results in an antidepressant effect, apparent even after the drug is no longer present in the bloodstream (Zarate et al., 2006).

Interestingly, while ketamine blocks a specific type of receptor in the brain (referred to as the NMDA receptor), the associated increase in the release of the brain chemical, glutamate, is believed to mediate many of its effects on brain function (Deakin et al., 2008) . Support for this idea comes from new magnetic resonance spectroscopy (MRS) findings linking ketamine-induced changes in cortical glutamate with the subjective effects of the drug (Stone et al., 2012). Thus understanding which neural circuits are modulated by ketamine may yield insights into putative mechanisms underlying the emergence of psychiatric disorders.

The Effects of Ketamine on Brain Networks
In order to visualise the brain regions responding to ketamine, brain imaging techniques can be used including functional magnetic resonance imaging (fMRI). In recent years the combination of MRI with drug administration has become increasingly popular. It is recognised as a method which enables researchers to map regional brain responses to drug administration, as well as the impact of drugs on brain circuits and networks. The generic term used to describe this approach, pharmacological MRI (phMRI) is commonly used to describe studies where subjects are scanned “at rest” whilst a drug is administered. However, phMRI can also be used to describe studies exploring drug-based modulation of the brain response when an individual is actively taking part in a cognitive test, for example a memory task.

In healthy humans who are scanned at rest, ketamine induces widespread increases in brain ‘activity’, with decreases in brain response in more specific areas located in frontal regions (De Simoni et al., 2013; Deakin et al., 2008).  These changes in the brain have also been shown to be predictive of the extent to which individuals experience ketamine-related subjective effects (as described above), supporting the connection between NMDA receptor blockade and schizophrenia-like symptoms. In addition, many of the effects were weakened by lamotrigine, a drug known to block glutamate release (Deakin et al., 2008).

Figure 1. The resting state brain response to  ketamine. Increases in activation are shown in  red, decreases in blue – De Simoni et al., 2012.
Figure 1. The resting state brain response to ketamine. Increases in activation are shown in red, decreases in blue. De Simoni et al., 2012.

Ketamine-induced modulation of cognitive brain networks has also been investigated in domains such as attention, memory, mental flexibility and learning. So far, most studies have explored ketamine-induced changes within localised brain regions and, irrespective of cognitive domain, ketamine tends to increase brain activation, primarily in areas central to memory and learning processes (Corlett et al., 2006; Daumann et al., 2008; Fu et al., 2005; G. D. Honey et al., 2005; R. A. Honey et al., 2004; Nagels, Kirner-Veselinovic, Krach, & Kircher, 2011). Although ketamine can also cause impairments in performance on a cognitive task, for example fewer items are remembered in a memory task than under normal conditions, changes in brain activation can occur in the absence of these impairments. This suggests that fMRI may be a more sensitive measure of changes in cognitive processes than performance with the additional benefit of elucidating compensatory mechanisms or strategies underlying the preserved performance.

The primary target of ketamine, the NMDA receptor, is essential for the changes in strength and efficiency  of short- and long-range connections within the brain. Disruption of this process may therefore influence how brain regions communicate with each other. Indeed, recent work has demonstrated that during performance of a working memory task, ketamine alters brain connectivity between networks which are normally active during task conditions (task ‘positive’ networks)  and the default mode network (DMN), a network of brain regions whose activation is normally suppressed during these same conditions (Anticevic et al., 2012).  DMN and circuit-level working memory abnormalities have in fact been found in schizophrenia (Schlosser et al., 2003; Whitfield-Gabrieli & Ford, 2012), highlighting the possibility that schizophrenia-related deficits arise from glutamatergically altered connections rather than a localised break down of function. However, an important next step is to clarify the relationship between the observed effects of ketamine on connectivity and the cognitive or subjective effect of the drug.

Why is ketamine research important?
The cognitive deficits seen in schizophrenia, due to their persistence over time, presence in first-degree relatives, and predictive value in terms of prognosis, are increasingly recognised as an important problem requiring treatment. As a result of the potential involvement of the glutamate system in this disorder, novel treatment strategies are targeting various aspects of this system. The value of ketamine as a probe of the glutamate system may also be relevant to depression whose neurobiological basis is also considered to involve glutamate. However, due to the physical, perceptual and cognitive side effects of ketamine, it may not be applicable for long-term clinical use. It is thus important to determine whether related compounds might have similar antidepressant efficacy while minimising side effects.
Ketamine-related imaging research is essential to these endeavours and is becoming ever more sophisticated in determining the role of the glutamatergic system in psychiatric disorders. Elucidating the neural basis of its effects could be extremely valuable not only in the development of new drugs but also in identification of markers that could inform the tailoring of treatment for personalized medicine.

References
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