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The present proposal aims to combine state-of-the-art integrated transcranial brain stimulation, electroencephalographic recording techniques with genetics and computational modeling to unveil the mechanisms underlying a fundamental cortical network process - synchronization of neuronal activity in the gamma band (30-80 Hz) - and the sources of its intersubject variability. By measuring the entrainment of prefrontal cortex produced by weak oscillatory currents, the study team will provide a new non-invasive strategy to derive robust estimates of the cortical ability to support gamma oscillations, critically overcoming limitations associated with current approaches and allowing measures solely dependent on intrinsic regional cortico-thalamic properties. Consistent with molecular evidence and the investigators biophysical models of gamma oscillations, the study team expects that such unambiguous measurement of cortical capabilities will straightforwardly map onto key genetic underpinnings related to the dopamine and neuregulin signaling pathways. These computational models will be used to offer critical mechanistic insights linking genetic variations to variability in emergent circuit-level activity in the form of cortical gamma oscillations.
The primary goal of the project is to study the effect of Ketamine on cortical neurophysiological function in Treatment Resistant Depression(TRD) patients. There are three key preclinical findings regarding Ketamine antidepressant effects that motivate the current study: a) low dose Ketamine causes early increase in glutamate neurotransmission; b) Ketamine initiates synaptic plasticity; c) ketamine infusion leads to rapid improvement in depression symptoms; d) specific expression and/or methylation markers measured in blood cells isolated treated ex vivo with ketamine will significantly correlate with the clinical response to treatment in patients with treatment-resistant depression; The proposal essentially employs robust and non-invasive neurophysiological techniques, Auditory Steady State Response(ASSR)-gamma oscillatory response and Transcranial Magnetic Stimulation(TMS) cortical excitability to investigate the above findings in patients with treatment resistant depression.
In the first session, one group of TRD patients receive low dose Ketamine (0.5 mg/kg) over 40 minutes while the other group of TRD patients receive placebo-saline infusion. In the second visit, the patients who received ketamine in the first visit will receive placebo-saline infusion and the patients who received placebo-saline infusion will receive a ketamine infusion. The study will be randomized such that in the first session, 5 patients will receive ketamine infusion and 5 patients will receive placebo. The randomization will be broken and the data analyzed. The study will then continue with the remaining 10 patients, where 5 of them will receive ketamine infusion and 5 patients will receive placebo infusion in the first session.
The study team will use slow infusions of ketamine/placebo-saline solution over a time period of 40 minutes. Study drug will be provided in identical syringes, containing clear solutions of 1 mL of ketamine, e.g. 100 mg/mL with 9 mL of normal saline or just 1 ml saline solution.
TMS stimulation will be applied to the corresponding region of the contralateral primary motor cortex to determine motor threshold and to examine the motor cortical excitability measures after Ketamine. The optimal coil position will be determined by moving the TMS coil in 1-cm increments over the motor cortical area while delivering single or paired magnetic pulses and by observing maximal contraction of the contralateral abductor pollicis brevis (APB). Electromyography readings will be obtained from the APB muscle. TMS stimulation will then be applied to Left DLPFC or Left Brodmann Area 6 to investigate cortical excitability changes after ketamine. Electroencephalography(EEG) recordings will be concurrent with TMS procedure.
Participants may engage in the auditory steady state response task where click trains of 500-ms duration will be presented binaurally at 65 ± 5 decibel(dB). The click train repetition frequencies will be 40 Hz and presented in the context of an auditory oddball paradigm to ensure participant attention to the stimuli. This task will be done while participants undergo EEG recordings.
Gene Expression and Methylation:
To identify alterations in gene expression and methylation markers induced by the ex vivo treatment of peripheral blood mononuclear cells from symptomatic patients with treatment-resistant depression with ketamine and assess their correlations with clinical response (as measured by the reduction in the Hamilton Depression Rating Scale - HDRS). For that end blood samples will be collected from all subjects immediately before the first administration of ketamine.
Brain-derived neurotrophic factor,(BDNF):
Serum BDNF tests will be performed. For that end blood samples will be collected from all subjects.
Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment
Treatment Resistant Depression
Ketamine, Saline solution
Harris County Psychiatric Center
Enrolling by invitation
The University of Texas Health Science Center, Houston
Published on BioPortfolio: 2016-10-18T02:08:21-0400
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Hypertonic sodium chloride solution. A solution having an osmotic pressure greater than that of physiologic salt solution (0.9 g NaCl in 100 ml purified water).
A cyclohexanone derivative used for induction of anesthesia. Its mechanism of action is not well understood, but ketamine can block NMDA receptors (RECEPTORS, N-METHYL-D-ASPARTATE) and may interact with sigma receptors.
An MAO inhibitor that is effective in the treatment of major depression, dysthymic disorder, and atypical depression. It also is useful in the treatment of panic disorder and the phobic disorders. (From AMA, Drug Evaluations Annual, 1994, p311)
A hallucinogen formerly used as a veterinary anesthetic, and briefly as a general anesthetic for humans. Phencyclidine is similar to KETAMINE in structure and in many of its effects. Like ketamine, it can produce a dissociative state. It exerts its pharmacological action through inhibition of NMDA receptors (RECEPTORS, N-METHYL-D-ASPARTATE). As a drug of abuse, it is known as PCP and Angel Dust.
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