Irving Reti MBBS

Associate Professor of Psychiatry and Behavioral Sciences

imreti@jhmi.edu
Telephone Number: 410-955-1484
Fax Number: 410-955-0152

The Johns Hopkins Hospital
Psychiatry
600 North Wolfe Street
Baltimore, MD 21205
Room: Meyer 3-181
Lab Page
Areas of Research
Systems, Cognitive + Computational Neuroscience
Neural Circuits, Ensembles + Connectomes

Graduate Program Affiliations

Neuroscience Training Program

Behavioral Neuroscience and its Clinical Applications

Basic 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.
 

Trsnslational Research:

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.


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