Filling the treatment gap: Ultrasonic thalamic stimulation in disorders of consciousness following severe brain injury

Dr. Martin M. Monti

University of California, Los Angeles

Department of Psychology
Funded in April, 2014: $300000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Ultrasound treatment to be tested in a small number of patients with disorders of consciousness

         Investigators will conduct the first clinical evaluation of the effects of using non-invasive Low Intensity Focused Ultrasound Pulsations to restore consciousness in a small number of severely head-injured adults. 

         Few disorders are as vexing and clinically and ethically challenging as disorders of consciousness. These disorders compose a set of related conditions—coma, vegetative state, and minimally conscious state-that primarily develop after severe head injury. Research over the past two decades has revealed that brain activity, including relatively high level cognitive processes, can remain in patients with disorders of consciousness. Moreover, tools used to diagnose these patients are prone to false negatives, meaning that some minimally conscious patients are incorrectly assessed as being in an unconscious (vegetative) state. 

         Recent efforts to experimentally restore consciousness are predicated on several related scientific bases. One is a theoretical understanding of the physiological processes that accompany the loss and recovery of consciousness following severe brain injury. This approach posits that there is a disconnection in brain circuitry that ordinarily links the brain’s thalamus and cortical areas, especially the prefrontal cortex in both brain hemispheres. 

         Preliminary data based on this approach suggest that deep brain stimulation (DBS) of brain circuits connecting the thalamus and cortical areas can lead to improvements in some patients with severe brain injury. While showing promise, this approach requires extensive imaging and other technologies to try to determine optimum surgical placement of electrodes in the thalamus. This procedure also requires intermittent battery replacement. 

         An alternative, non-invasive, approach involves the use of Low Intensity Focused Ultrasound Pulsations (LIFUP) in the brain’s thalamus. Ultrasound waves penetrate the skull, and produce highly focused stimulation (or inhibition) of brain activity that is reversible. When LIFUP is used with fMRI imaging, the combination provides real-time information on brain functioning; and when used with EEG (electroencephalography, which measures global and regional electrical activity in the brain), there is the potential to determine how LIFUP stimulation achieves its effects. 

         A UCLA team has tested LIFUP in animal models. This team consists of investigators with expertise in neuroimaging, DBS, LIFUP and other neuromodulation interventions, brain mapping of connectivity, and in critical care of brain injured patients. They have found preliminary evidence in the animal model that LIFUP can: 1) stimulate motor activity; 2) moderate neural activation in the brain’s hippocampus (involved in memory) and in the hypothalamus (which controls a number of autonomic body and endocrine functions); and 3) disrupt seizures. 

         A similar ultrasound intervention has been used by other investigators in a small clinical study in patients with tremor. Those clinical researchers used high intensity focused ultrasound, which employs higher energy levels than LIFUP, and demonstrated initial evidence of the technique’s safety. 

         Based on the UCLA team’s animal research and the related human study, the investigators hypothesize that human thalamic LIFUP stimulation: 1) will be safe; 2) can increase patients’ awareness/arousal to an extent that is at least comparable to that produced by thalamic DBS, by inducing functional and structural changes in the involved brain circuitry; and 3) will benefit patients only if their brain structures and connectivity within the circuitry—especially between thalamus and prefrontal cortex—are sufficiently preserved, and there is sufficient functional activity to support brain plasticity. 

         They will test these hypotheses in this first in human study of LIFUP, which will involve a small number of patients suffering from disorders of consciousness that developed following severe brain injury. Using LIFUP stimulation of the brain’s thalamus, they will develop initial information on the intervention’s safety, potential effectiveness, and on the physiological processes that underlie LIFUP’s effects or lack of effects. 

         To accomplish these aims, patients will be assessed prior to the first use of LIFUP (baseline), and before and after LIFUP stimulation performed at three, six, and twelve months thereafter. At each of these times, patients will receive: standard clinical testing (including the Coma recovery Scale and Glasgow Coma Outcome Scale). They also will undergo imaging with MRI, fMRI and DTI (diffusion-tensor imaging of the brain’s white matter axons that connect brain regions) to assess stimulation-related changes in behavior, diagnosis, and structure and function within the targeted brain circuitry. 

         Additionally during LIFUP treatment, they will collect EEG data to assess how LIFUP stimulation works (its “mechanism of action” on neurons). The results may demonstrate the presence of neurobiological markers that signal: 1) the patient’s susceptibility to treatment; 2) real- time changes in brain function during LFIUP stimulation; 3) functional and structural changes induced by LIFUP stimulation; and 4) the extent to which these functional and structural changes correlate with clinical and behavioral alterations. 

         Comments from leading researchers who have pioneered DBS therapy in patients with disorders of consciousness consider this research by a first-rate team to be potentially highly rewarding if successful and if meaningful results are obtained by targeting deep subcortical brain structures in patients; and, a valuable result if they are able to demonstrate that the technique can produce undisputed patterns of activation of the cortex in both brain hemispheres. 

         Potential Challenges and Benefits: Research in patients with disorders of consciousness poses clinical and ethical challenges because patients are by definition not able to provide informed consent and family members must make difficult decisions based on their understanding of the potential benefits and risks. The investigators have the benefit of using ethical guidelines for such research that were developed through a prior Dana grant to Cornell University. If this study is able to demonstrate proof-of-concept of this potential non-invasive restorative intervention, it would lead to larger scale clinical studies that might ultimately benefit patients with these devastating conditions and those who care for them. 

         Significance: This study ultimately could lead to development of LIFUP as an effective non- invasive intervention to restore consciousness in patients who meet the clinical criteria.     

ABSTRACT

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Filling the treatment gap: Ultrasonic thalamic stimulation in disorders of consciousness following severe brain injury

Few neurological conditions are as scientifically mysterious and clinically, legally and ethically challenging as disorders of consciousness (DOC). Typically developed after severe brain injury, this set of related conditions includes Coma, the Vegetative State (VS) and the Minimally Conscious State (MCS). Despite an increasingly growing amount of research in this field, to date there still exist no standard treatments for patients suffering from these conditions. Recent data suggests that DOC might be understood as a pathology of cortico-subcortical circuits uniting frontal and parietal lobes to subcortical nuclei, and particularly thalamus. Indeed, we have recently shown that targeted atrophy within these regions is visible in chronic patients, and occurs (at least in part) within the first few months post-injury. A small number of case reports have shown that invasive stimulation within thalamus, using deep brain stimulation (DBS), can ameliorate the patient’s level of responsiveness. However, DBS is an invasive and risky procedure which limits its application as a therapeutic intervention. The present project is thus aimed at filling the treatment gap by evaluating, for the first time in humans, the potential of non-invasive thalamic Low Intensity Focused Ultrasound Pulsations (LIFUP) as a neuro-restorative treatment. In particular, we propose to set up a longitudinal clinical study, in a small number of patients suffering from DOC, to assess whether this proposed intervention is safe and whether it can induce results at least comparable to invasive interventions. In addition, evaluating patients with structural and functional neuroimaging (i.e., functional and structural magnetic resonance imaging, and electroencephalography) before and after interventions, we will also assess the physiological mechanisms affected by the stimulation. If successful, this project has the potential of opening a completely new avenue for therapy and care-taking in patients suffering from this devastating condition for which there currently is no standard intervention.

INVESTIGATOR BIOGRAPHIES

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Dr. Martin M. Monti

Martin M. Monti is assistant professor in the Departments of Psychology and Neurosurgery at University of California Los Angeles (USA). After graduating in Economics at Università L Bocconi in Milan, Italy, he was awarded a Ph.D. in Psychology and Neuroscience from Princeton University. Prior to joining the faculty at UCLA Dr. Monti spent three years in Cambridge UK as a post-doctoral scientist at the Medical Research Council – Cognition and Brain Sciences Unit. Dr. Monti’s research employs neuroimaging methods (functional and structural magnetic resonance imaging) to assess the neural mechanisms that underlie disorders of consciousness such as Coma, the Vegetative State and the Minimally Conscious State. In particular, he is interested in the changes in brain structure and function that accompany the loss and (sometimes) recovery of consciousness after severe brain injury. Dr. Monti’s research in the domain of Disorders of Consciousness has been recently recognized with a “Rising Star” award by the Association for Psychological Science, as well as the UCLA Life Science Award for Outstanding Research Publication, and has been widely featured in international press.