Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action

Abstract

Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the „dorsal nexus “(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.

Sleep deprivation increases dorsal nexus connectivity to the dorsolateral prefrontal cortex in humans

“…Here, we offer a neurobiological explanation for the known antidepressive action of sleep deprivation. using a seed region identical to a previous work (center of this region: x = −8, y = −49, z = 28) (23). It is important to note that, consistent with previous studies (22,24), sleep deprivation reduced functional connectivity of the PCC with the ACC (BA 32; coordinates: +5, +43, +3; z score = 3.7173, P = 0.000201; cluster size = 359 mm 3 ) (Fig.…”

“…The first revealed reduced functional connectivity between DN and hippocampus after 7 d of citalopram administration (35). The second showed reduced DN connectivity with the PCC and the pregenual ACC 24 h after ketamine infusions (23). These studies support the hypothesis that reducing DN connectivity to subcortical structures and the DMN network may represent a biomechanism of antidepressant action.…”

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning, but Ketamine Abolishes those Effects

“…Antidepressant doses of ketamine decreased the default mode connectivity (Scheidegger et al, 2012) and reduced core symptoms of PTSD, including avoidance (Feder et al, 2014). Based on these observations in humans and our findings in mice, we hypothesize that silent synapses underlie the enhanced functional connectivity in mental disease, whereas positive effects of ketamine result from their elimination.…”

“…Studies of humans revealed enhanced functional connectivity between the anterior cingulate cortex and right amygdala in PTSD (Lanius et al, 2010) and within the default mode network in depression (Scheidegger et al, 2012). Antidepressant doses of ketamine decreased the default mode connectivity (Scheidegger et al, 2012) and reduced core symptoms of PTSD, including avoidance (Feder et al, 2014).…”

Resting state glutamate predicts elevated pre-stimulus alpha during self-relatedness: A combined EEG-MRS study on “rest-self overlap”

“…Although inhibitory GABA has recently been shown to mediate EEG taskevoked measures like gamma band oscillations (Lally et al, 2014;Muthukumaraswamy, Edden, Jones, Swettenham, & Singh, 2009), studies on excitatory glutamate modulation of EEG measures have been reported less widely (for exceptions, see Lally et al, 2014; for animal studies, see MoralesVillagrán, Medina-Ceja, & López-Pérez, 2008). Glutamate is an excitatory transmitter that fMRI and magnetic resonance spectroscopy (MRS) analyses have shown to mediate resting state activity, including both intra-regional activity levels and trans-regional functional levels (Duncan, Enzi, Wiebking, & Northoff, 2011;Duncan et al, 2013;Enzi et al, 2012; also see Falkenberg, Westerhausen, Specht, & Hugdahl, 2012;Scheidegger et al, 2012). Such glutamatergic modulation of the resting state suggests that glutamate might mediate the influence of pre-stimulus state activity on stimulus-related activity.…”