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Brain Stimulation Research

Electroconvulsive therapy (ECT) is far and away the most effective treatment for severe depression, however little is known about how it works. Learning more about how ECT works is important for several reasons. It might help us optimize ECT technique that maximizes efficacy and minimizes memory loss associated with the treatment. Understanding the ECT mechanism of action could help guide the development of other potentially efficacious treatments for depression and other conditions, both pharmacologic and somatic. Such treatments ideally would not trigger the cognitive side effects of ECT nor require anesthesia. Lastly, if we knew how ECT worked, it could help shed light on the pathophysiology of conditions treated with ECT.

The antidepressant response to ECT

A key feature of ECT is the speed at which depressed patients respond. Neuronal immediate early genes are rapidly and robustly induced by ECT and other stimuli in rodent models and have been shown to play key roles in enduring forms of synaptic plasticity. Accordingly, they represent a mechanism by which a brief seizure could elicit longer-term adaptations in neuronal function that underlie the rapid antidepressant effect of ECT. We have focused on one of these immediate early genes, Narp, which clusters AMPA receptors and is expressed selectively in limbic brain regions regulating mood and motivation. We have found that mice which lack Narp fail to develop expected behavioral responses in standard rodent antidepressant behavioral assays after a brief course of ECT. These mice also fail to develop normal dendritic arborization in the hippocampus following ECT. Ongoing studies are focused on whether Narp knockout mice develop the expected amnesia after ECT, as well as why such behavioral deficits develop in these mice following ECT.

ECT for suppressing intractable self-injurious behavior

About a quarter of individuals with autism spectrum disorder display repetitive self-injurious behavior (SIB) including head banging and self-directed biting and punching. In some patients, these behaviors are extreme and unresponsive to traditional pharmacological and behavioral therapies with devastating consequences for the patients and their families. We have found ECT can produce life-changing results with a greater than 90% reduction in frequency of SIB in patients with the most severe forms of self-injury. However, these patients typically require frequent maintenance ECT (mECT) to sustain the improvement gained during the acute ECT course. Such mECT regimes can be as frequent as one treatment every 5 days. However, ECT is associated with cognitive side effects and the long-term consequences of mECT started as early as childhood in some cases are unknown. Accordingly, we are interested in learning more about how ECT works in these patients and developing alternate forms of brain stimulation which could potentially suppress SIB without the side effects associated with ECT.

To this end, we are using autism-like mouse models which display excessive stereotyped self-grooming. We are evaluating the response of these mice to ECT and to deep brain stimulation (DBS). In one set of experiments, we are characterizing changes in the levels of the inhibitory neurotransmitter GABA in the striatum and assessing whether these changes match the ability of ECT to suppress excessive self-grooming in genetically distinct strains of mice. In another set of experiments, we have found that DBS at the subthalamic nucleus suppresses excessive self-grooming. In follow-up experiments, we are utilizing an optogenetics-based approach to determine which pathways mediate the DBS response.

Clinical research in brain stimulation

Although ECT is one of the oldest and most established treatments in psychiatry, we and others have continued to study how we can improve its efficacy and decrease cognitive side-effects associated with the treatment. We have also focused on other brain stimulation modalities, most notably transcranial magnetic stimulation (TMS), and have led and participated in clinical trials utilizing both modalities. Current projects include:

(a) A comparison of the antidepressant response and side effects of ECT and ketamine.
(b) Genetics factors predicting response to ECT.
(c) Development of TMS for suppressing intractable self-injurious behavior associated with intellectual and developmental disabilities.
(d) A comparison of the antidepressant response to TMS delivered via the figure-of-8 versus the H-coil.

Enrollment for these studies is by invitation only.
For more information, please call 410-614-1732 or email Michael Tibbs at mtibbs@jhmi.edu

Recent Publications

Reti IM and Baraban JM (2000): Sustained increase in Narp protein expression following repeated electroconvulsive seizure. Neuropsychopharmacology. 23: 439-43.

Wachtel LE, Kahng SW, Cascella N, Dhossche DM, Reti IM (2008): Electroconvulsive Therapy for Severe Catatonic Deterioration in an Autistic Girl with Mental Retardation and Self-injury: A Case Report. American Journal of Psychiatry, 165: 329-33.

Anderson E and Reti IM (2009). ECT in Pregnancy: A Review of the Literature from 1941 to 2007. Psychosomatic Medicine, 71: 235-242.

Reti IM, Walker M, Pulia K, Gallegos J, Jayaram G, Vaidya P (2012). Safety considerations for outpatient electroconvulsive therapy. Journal of Psychiatric Practice, 18:130-6.

Tripathi A, Winek N, Goel K, D’Agati D, Gallegos J, Jayaram G, Ngyugen T, Vaidya P, Zandi P, Trivedi JK, Reti IM (2014). Electroconvulsive therapy pre-treatment with low dose propofol: comparison with unmodified treatment. Journal of Psychiatric Research, 53: 173-9.

Reti IM, Schwarz N, Bower A, Tibbs M, Rao­ V (2015). Transcranial magnetic stimulation: a potential new treatment for depression associated with traumatic brain injury. Brain Injury, 29: 789-97.

Brain Stimulation: Methodologies and Interventions. Editor – Reti IM, Wiley Blackwell (2015).

Chang AD, Berges VA, Chung JS, Fridman GY, Baraban JM, Reti IM (2016). High frequency stimulation at the subthalamic nucleus suppresses excessive self-grooming in autism-like mouse models. Neuropsychopharmacology, 41(7): 1813-21.

McClintock SM, Reti IM, Carpenter LL, McDonald WM, Dubin M, Taylor SF, Cook IA, O'Reardon J,  Husain MM, Wall C, Krystal A, Sampson S, Morales O, Nelson BG, Latoussakis V, George MS, Lisanby SH (2018). Consensus Recommendations for the Clinical Application of Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Depression. Journal of Clinical Psychiatry, Jan/Feb 79(1).

Weiner RD and Reti IM (2017). Key updates in the clinical application of electroconvulsive therapy. International Review of Psychiatry. 29(2): 54–62.

Chang AD, Vaidya PV, Retzbach EP, Chung SJ, Kim U, Baselice K, Maynard K, Stepanian A, Staley M, Xiao L, Blouin A, Han S, Lee JJ, Worley PF, Tamashiro KL, Hempstead BL, Martinowich K, Wilson MA, Baraban JM, Reti IM (2018). Narp mediates antidepressant-like effects of electroconvulsive seizures, Neuropsychopharmacology, 43(5): 1088-98.

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