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Basic Science 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.
A key feature of ECT is the speed at which 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 long-term adaptations in neuronal function that underlie the therapeutic effects 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. Ongoing studies, utilizing viral vectors and other techniques, are focused on understanding why these mice fail to develop an antidepressant response to ECT.
Between a third and half of autistic individuals display repetitive self-injurious behavior (SIB) ranging from head banging to 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 electroconvulsive therapy (ECT) can produce life-changing results with a greater than 90% reduction in frequency of autistic SIB in patients with the most severe forms of self-injury. However, these patients typically require 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 developing alternate forms of brain stimulation which could potentially suppress SIB without the side effects associated with ECT.
To evaluate the utility of deep brain stimulation (DBS) for autistic SIB, we have used a mouse model (Viaat-Mecp2-/y) which displays excessive stereotyped self-grooming with development of skin lesions and social deficits. We have found that a single electroconvulsive seizure significantly suppresses their excessive self-grooming, similar to the positive effect of ECT observed in the clinic. In order to test whether DBS could also suppress excessive self-grooming in these mice, we have targeted the subthalamic nucleus (STN), and found that STN-DBS both acutely and chronically suppresses the behavior, reminiscent of STN-DBS suppressing repetitive stereotyped behaviors in monkeys and treatment refractory obsessive compulsive disorder in patients.
Ongoing and future studies include: (a) utilizing alternate autistic mouse models with distinct genetic etiologies, (b) comparing the effectiveness of DBS targeting several candidate sites, (c) employing optogenetic stimulation to learn more about the circuitry harnessed by DBS that suppresses excessive self-grooming. In addition we have begun working with a cohort of monkeys which exhibit SIB to learn if they also respond to ECT and whether they could serve as a model for autistic SIB. These translational studies should yield valuable insights into optimized targeting and stimulation for suppressing autistic SIB in patients using invasive brain stimulation such as DBS or epidural cortical stimulation. They should also provide clues about brain circuitry which might be harnessed by non-invasive neuromodulatory techniques such as transcranial magnetic stimulation and transcranial direct current stimulation. Finally, they could also yield insights about targets for reducing SIB associated with other conditions including Lesch-Nyhan, Fragile X and Tourette’s Syndromes.
Although ECT is one the oldest and most established treatments in psychiatry, even in recent years we have continued to learn how we can improve its efficacy and decrease cognitive side-effects associated with the treatment such as by using high dose right unilateral treatment and ultrabrief pulsewidth stimulation. Our team is examining several different aspects of ECT delivery to learn how we can affect and improve on these outcome measures.
Clinical Trial of TMS with Mood Stabilizers in Bipolar Depression
If you are between the ages of 22-68, currently suffering from Bipolar depression, and are currently taking a mood stabilizer you may be eligible to participate in a research study on deep Transcranial Magnetic Stimulation (dTMS). This study is being conducted to evaluate the safety and effectiveness of the H-Coil Transcranial Magnetic Stimulation (TMS) in treating bipolar depression. Participation involves 25 visits over 8 weeks. There are up to three weeks for screening visits to determine eligibility. During this time participants will also need to be gradually taken off of psychiatric medications except for a mood stabilizer. Once eligible, there are 8 weeks of the study procedure including 2 follow-up visits. Participants will have a 50% chance of receiving real TMS or sham TMS once a day, 5 days per week for 4 consecutive weeks, then 3 times during week 5, and once during week 6. Participant safety will be monitored, and each participant will be asked questions pertaining to their mood and anxiety. There will be compensation for participating in this study. For more information please call 410-614-1732. The principal investigator is Dr. Irving Reti. (IRB Protocol # NA_00045624).
Clinical Trial of TMS for Depression after Traumatic Brain Injury
If you are 18 years or older, with a history of closed head injury at least 3 months ago and followed by a diagnosis of depression or symptoms of depression, you may be eligible to participate in a research study on Transcranial Magnetic Stimulation (TMS). This study is being conducted to evaluate the safety and effectiveness of TMS in treating post-TBI depression. Participation involves 27 visits over 16 weeks for eligibility screening, device sessions, and follow-ups. Prior to enrolling, participants will also need to be gradually taken off of psychiatric medications. Participants will have a 50% chance of receiving real TMS or sham TMS once a day, 5 days per week for 4 consecutive weeks. Participant safety will be monitored, and each participant will be asked questions pertaining to their mood and other neuropsychiatric symptoms. There will be compensation for participating in this study. For more information please call 410-550-9053. The principal investigator is Dr. Vani Rao. (IRB Protocol # NA_00090926).
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)