Ketamine Effects on Energy Metabolism, Functional Connectivity and Working Memory in Healthy Humans.

Working memory (WM) is a crucial resource for temporary memory storage and the guiding of ongoing behavior. N-methyl-D-aspartate glutamate receptors (NMDARs) are thought to support the neural underpinnings of WM. Ketamine is an NMDAR antagonist that has cognitive and behavioral effects at subanesthetic doses. To shed light on subanesthetic ketamine effects on brain function, we employed a multimodal imaging design, combining gas-free calibrated functional magnetic resonance imaging (fMRI) measurement of oxidative metabolism (CMRO 2 ), resting-state cortical functional connectivity assessed with fMRI, and WM-related fMRI. Healthy subjects participated in two scan sessions in a randomized, double-blind, placebo-controlled design. Ketamine increased CMRO 2 and cerebral blood flow (CBF) in prefrontal cortex (PFC) and other cortical regions. However, resting-state cortical functional connectivity was not affected. Ketamine did not alter CBF-CMRO 2 coupling brain-wide. Higher levels of basal CMRO 2 were associated with lower task-related PFC activation and WM accuracy impairment under both saline and ketamine conditions. These observations suggest that CMRO 2 and resting-state functional connectivity index distinct dimensions of neural activity. Ketamine’s impairment of WM-related neural activity and performance appears to be related to its ability to produce cortical metabolic activation. This work illustrates the utility of direct measurement of CMRO 2 via calibrated fMRI in studies of drugs that potentially affect neurovascular and neurometabolic coupling.

A robust and reproducible connectome fingerprint of ketamine is highly associated with the connectomic signature of antidepressants.

Over the past decade, various N-methyl-D-aspartate modulators have failed in clinical trials, underscoring the challenges of developing novel rapid-acting antidepressants based solely on the receptor or regional targets of ketamine. Thus, identifying the effect of ketamine on the brain circuitry and networks is becoming increasingly critical. In this longitudinal functional magnetic resonance imaging study of data from 265 participants, we used a validated predictive model approach that allows the full assessment of brain functional connectivity, without the need for seed selection or connectivity summaries. First, we identified a connectome fingerprint (CFP) in healthy participants (Cohort A, n = 25) during intravenous infusion of a subanesthetic dose of ketamine, compared to normal saline. We then demonstrated the robustness and reproducibility of the discovered ketamine CFP in two separate healthy samples (Cohort B, n = 22; Cohort C, n = 18). Finally, we investigated the ketamine CFP connectivity at 1-week post treatment in major depressive disorder patients randomized to 8 weeks of sertraline or placebo (Cohort D, n = 200). We found a significant, robust, and reproducible ketamine CFP, consistent with reduced connectivity within the primary cortices and within the executive network, but increased connectivity between the executive network and the rest of the brain. Compared to placebo, the ketamine CFP connectivity changes at 1 week predicted response to sertraline at 8 weeks. In each of Cohorts A-C, ketamine significantly increased connectivity in a previously identified antidepressant CFP. Investigating the brain connectivity networks, we successfully identified a robust and reproducible ketamine biomarker that is related to the mechanisms of antidepressants.

Altered functional connectivity and low-frequency signal fluctuations in early psychosis and genetic high risk.

Studying individuals at increased genetic risk for schizophrenia may generate important theories regarding the emergence of the illness. In this investigation, genetic high-risk individuals (GHR, n = 37) were assessed with functional magnetic resonance imaging and compared to individuals in the first episode of schizophrenia (FESZ, n = 42) and healthy comparison subjects (HCS, n = 59). Measures of functional connectivity and the amplitude of low-frequency fluctuation (ALFF) were obtained in a global, data-driven analysis. The functional connectivity measure, termed degree centrality, assessed each voxel's connectivity with all the other voxels in the brain. GHR and FESZ displayed increased degree centrality globally and locally. On ALFF measures, GHR were indistinguishable from HCS in the majority of areas but resembled FESZ in insula, basal ganglia and hippocampus. FESZ evidenced reduced amplitude of the global neural signal as compared to HCS and GHR. Results support the hypothesis that schizophrenia diathesis involves functional connectivity and ALFF abnormalities. In addition, they further an emerging theory suggesting that increased connectivity and metabolism may be involved in schizophrenia vulnerability and early stages of the illness.

Impaired Tuning of Neural Ensembles and the Pathophysiology of Schizophrenia: A Translational and Computational Neuroscience Perspective.

The functional optimization of neural ensembles is central to human higher cognitive functions. When the functions through which neural activity is tuned fail to develop or break down, symptoms and cognitive impairments arise. This review considers ways in which disturbances in the balance of excitation and inhibition might develop and be expressed in cortical networks in association with schizophrenia. This presentation is framed within a developmental perspective that begins with disturbances in glutamate synaptic development in utero. It considers developmental correlates and consequences, including compensatory mechanisms that increase intrinsic excitability or reduce inhibitory tone. It also considers the possibility that these homeostatic increases in excitability have potential negative functional and structural consequences. These negative functional consequences of disinhibition may include reduced working memory-related cortical activity associated with the downslope of the "inverted-U" input-output curve, impaired spatial tuning of neural activity and impaired sparse coding of information, and deficits in the temporal tuning of neural activity and its implication for neural codes. The review concludes by considering the functional significance of noisy activity for neural network function. The presentation draws on computational neuroscience and pharmacologic and genetic studies in animals and humans, particularly those involving N-methyl-D-aspartate glutamate receptor antagonists, to illustrate principles of network regulation that give rise to features of neural dysfunction associated with schizophrenia. While this presentation focuses on schizophrenia, the general principles outlined in the review may have broad implications for considering disturbances in the regulation of neural ensembles in psychiatric disorders.

N-methyl-D-aspartate receptor antagonist effects on prefrontal cortical connectivity better model early than chronic schizophrenia.

BACKGROUND: Prefrontal cortex (PFC) function contributes to schizophrenia onset and progression. However, little is known about neural mechanisms behind PFC functional alterations along illness stages. Recent pharmacologic studies indicate that glutamate dysfunction may produce increased functional connectivity. However, pharmacologic models of schizophrenia overlook effects of illness progression on PFC function. This study compared N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist effects in healthy volunteers with stages of schizophrenia with respect to PFC functional connectivity. METHODS: First, we tested ketamine effects on PFC functional connectivity in healthy volunteers in a data-driven way (n = 19). Next, we compared healthy subjects (n = 96) with three clinical groups: individuals at high risk for schizophrenia (n = 21), people early in their course of schizophrenia (EC-SCZ) (n = 28), and patients with chronic illness (n = 20). Across independent analyses, we used data-driven global brain connectivity techniques restricted to PFC to identify functional dysconnectivity. RESULTS: Results revealed robust PFC hyperconnectivity in healthy volunteers administered ketamine (Cohen's d = 1.46), resembling individuals at high risk for schizophrenia and EC-SCZ. Hyperconnectivity was not found in patients with chronic illness relative to EC-SCZ patients. Results provide the first evidence that ketamine effects on PFC functional connectivity resemble early course but not chronic schizophrenia. CONCLUSIONS: Results suggest an illness phase-specific relevance of NMDAR antagonist administration for prefrontal dysconnectivity associated with schizophrenia. This finding has implications for the neurobiology of illness progression and for the widespread use of NMDAR antagonists in the development of therapeutics for schizophrenia.

The impact of NMDA receptor blockade on human working memory-related prefrontal function and connectivity.

Preclinical research suggests that N-methyl-D-aspartate glutamate receptors (NMDA-Rs) have a crucial role in working memory (WM). In this study, we investigated the role of NMDA-Rs in the brain activation and connectivity that subserve WM. Because of its importance in WM, the lateral prefrontal cortex, particularly the dorsolateral prefrontal cortex and its connections, were the focus of analyses. Healthy participants (n=22) participated in a single functional magnetic resonance imaging session. They received saline and then the NMDA-R antagonist ketamine while performing a spatial WM task. Time-course analysis was used to compare lateral prefrontal activation during saline and ketamine administration. Seed-based functional connectivity analysis was used to compare dorsolateral prefrontal connectivity during the two conditions and global-based connectivity was used to test for laterality in these effects. Ketamine reduced accuracy on the spatial WM task and brain activation during the encoding and early maintenance (EEM) period of task trials. Decrements in task-related activation during EEM were related to performance deficits. Ketamine reduced connectivity in the DPFC network bilaterally, and region-specific reductions in connectivity were related to performance. These results support the hypothesis that NMDA-Rs are critical for WM. The knowledge gained may be helpful in understanding disorders that might involve glutamatergic deficits such as schizophrenia and developing better treatments.

Connectivity, pharmacology, and computation: toward a mechanistic understanding of neural system dysfunction in schizophrenia.

Neuropsychiatric diseases such as schizophrenia and bipolar illness alter the structure and function of distributed neural networks. Functional neuroimaging tools have evolved sufficiently to reliably detect system-level disturbances in neural networks. This review focuses on recent findings in schizophrenia and bipolar illness using resting-state neuroimaging, an advantageous approach for biomarker development given its ease of data collection and lack of task-based confounds. These benefits notwithstanding, neuroimaging does not yet allow the evaluation of individual neurons within local circuits, where pharmacological treatments ultimately exert their effects. This limitation constitutes an important obstacle in translating findings from animal research to humans and from healthy humans to patient populations. Integrating new neuroscientific tools may help to bridge some of these gaps. We specifically discuss two complementary approaches. The first is pharmacological manipulations in healthy volunteers, which transiently mimic some cardinal features of psychiatric conditions. We specifically focus on recent neuroimaging studies using the NMDA receptor antagonist, ketamine, to probe glutamate synaptic dysfunction associated with schizophrenia. Second, we discuss the combination of human pharmacological imaging with biophysically informed computational models developed to guide the interpretation of functional imaging studies and to inform the development of pathophysiologic hypotheses. To illustrate this approach, we review clinical investigations in addition to recent findings of how computational modeling has guided inferences drawn from our studies involving ketamine administration to healthy subjects. Thus, this review asserts that linking experimental studies in humans with computational models will advance to effort to bridge cellular, systems, and clinical neuroscience approaches to psychiatric disorders.

NMDA receptor function in large-scale anticorrelated neural systems with implications for cognition and schizophrenia.

Glutamatergic neurotransmission mediated by N-methyl-d-aspartate (NMDA) receptors is vital for the cortical computations underlying cognition and might be disrupted in severe neuropsychiatric illnesses such as schizophrenia. Studies on this topic have been limited to processes in local circuits; however, cognition involves large-scale brain systems with multiple interacting regions. A prominent feature of the human brain's global architecture is the anticorrelation of default-mode vs. task-positive systems. Here, we show that administration of an NMDA glutamate receptor antagonist, ketamine, disrupted the reciprocal relationship between these systems in terms of task-dependent activation and connectivity during performance of delayed working memory. Furthermore, the degree of this disruption predicted task performance and transiently evoked symptoms characteristic of schizophrenia. We offer a parsimonious hypothesis for this disruption via biophysically realistic computational modeling, namely cortical disinhibition. Together, the present findings establish links between glutamate's role in the organization of large-scale anticorrelated neural systems, cognition, and symptoms associated with schizophrenia in humans.

Impairment of working memory maintenance and response in schizophrenia: functional magnetic resonance imaging evidence.

BACKGROUND: Comparing prefrontal cortical activity during particular phases of working memory in healthy subjects and individuals diagnosed with schizophrenia might help to define the phase-specific deficits in cortical function that contribute to cognitive impairments associated with schizophrenia. This study featured a spatial working memory task, similar to that used in nonhuman primates, that was designed to facilitate separating brain activation into encoding, maintenance, and response phases. METHODS: Fourteen patients with schizophrenia (4 medication-free) and 12 healthy comparison participants completed functional magnetic resonance imaging while performing a spatial working memory task with two levels of memory load. RESULTS: Task accuracy was similar in patients and healthy participants. However, patients showed reductions in brain activation during maintenance and response phases but not during the encoding phase. The reduced prefrontal activity during the maintenance phase of working memory was attributed to a greater rate of decay of prefrontal activity over time in patients. Cortical deficits in patients did not appear to be related to antipsychotic treatment. In patients and in healthy subjects, the time-dependent reduction in prefrontal activity during working memory maintenance correlated with poorer performance on the memory task. CONCLUSIONS: Overall, these data highlight that basic research insights into the distinct neurobiologies of the maintenance and response phases of working memory are of potential importance for understanding the neurobiology of cognitive impairment in schizophrenia and advancing its treatment.

Hypoglycemia reduces the blood-oxygenation level dependent signal in primary auditory and visual cortex: a functional magnetic resonance imaging study.

Studies of the effects of hypoglycemia on the brain using neurocognitive testing have suggested that mainly complex functions subserved by secondary and tertiary cortex are affected by mild to moderate hypoglycemia and that intensively treated patients with Type I diabetes mellitus (T1DM) may have altered sensitivity to the central nervous system effects of hypoglycemia. Functional magnetic resonance imaging provides a sensitive, regionally-specific probe of possible neurophysiologic changes related to hypoglycemia in the brain. Eleven intensively-treated T1DM patients and 11 matched non-diabetic controls took part in a 2-day protocol in which functional magnetic resonance imaging (MRI) was used to measure changes in the patterns of brain activation produced by simple auditory and visual stimuli in different conditions. On one day, participants were euglycemic the entire time. On the other day, an initial 50-min euglycemic period was followed by a 50-min hypoglycemic period. Results indicated that hypoglycemia reduced the amplitude of the blood-oxygenation level dependent response in primary auditory and visual cortex to simple auditory and visual stimuli. The latency and duration of the transient hemodynamic response function were not affected. Responses to hypoglycemia were similar in diabetic and non-diabetic participants. These results suggest that mild to moderate hypoglycemia may alter the balance of blood flow and oxygen extraction when glucose levels are lowered. Intensively-treated T1DM, with its attendant frequent hypoglycemic episodes, did not seem to alter hypoglycemic responses in primary visual and auditory cortex.

Brain connectivity related to working memory performance.

Several brain areas show signal decreases during many different cognitive tasks in functional imaging studies, including the posterior cingulate cortex (PCC) and a medial frontal region incorporating portions of the medial frontal gyrus and ventral anterior cingulate cortex (MFG/vACC). It has been suggested that these areas are components in a default mode network that is engaged during rest and disengaged during cognitive tasks. This study investigated the functional connectivity between the PCC and MFG/vACC during a working memory task and at rest by examining temporal correlations in magnetic resonance signal levels between the regions. The two regions were functionally connected in both conditions. In addition, performance on the working memory task was positively correlated with the strength of this functional connection not only during the working memory task, but also at rest. Thus, it appears these regions are components of a network that may facilitate or monitor cognitive performance, rather than becoming disengaged during cognitive tasks. In addition, these data raise the possibility that the individual differences in coupling strength between these two regions at rest predict differences in cognitive abilities important for this working memory task.