Amit Etkin - US grants

DESCRIPTION (provided by applicant): Recent studies have found that the mechanisms of learning, and those of long-term potentiation (LTP), can differ, depending on induction protocol used. It has long been known that the formation of new memories and LTP require the synthesis of new proteins, a process regulated by constitutively expressed transcription factors. Disruptions of CREB, the most prominent such factor, however, have failed to completely abolish memory and synaptic plasticity, suggesting the existence of multiple transcriptional pathways. This proposal seeks to determine what the role of another transcriptional enhancer system, the serum response element (SRE), is in long-term memory and synaptic plasticity, and determine if it cooperates with the cyclic-AMP responsive element (CRE, bound by CREB) in these processes. In order to so so, experiments are proposed using mice carrying a region-specific, regulated dominant-negative SRF transgene (the core transcription factor necessary for SRE function). In addition, we propose further experiments to achieve better temporal resolution of SRE effect, using a technique for acute, high-efficiency knockdown of the entire enhancer in vivo and in vitro. Answers to the questions posed will elucidate the role of the SRE in long-term memory and synaptic plasticity, thus representing a possible therapeutic target. In addition, the acute method developed in these experiments will allow knockdown of any enhancer system in any experimental animal, which has relevance both to the study of molecules in non-manipulateable species, and to human therapies.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Individuals with anxiety or mood disorders experience exaggerated or inappropriate emotional reactions, often despite deliberate and effortful attempts at emotion regulation. In this talk I will describe a limbic-medial prefrontal circuit involved in evaluating and regulating emotion outside of awareness, using a task employing salient emotionally conflicting stimuli.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Despite decades of imaging research, the brain basis of major depression remains ill-defined. Limited understanding of the underlying mechanisms has resulted in a trial and error approach to treatment which can result in prolonged delays and exposure to potentially avoidable side-effects. This study proposes using a novel imaging approach, resting-state functional connectivity to 1) enhance our understanding of the brain bases of the affective and cognitive symptoms of depression and 2) develop an objective fMRI biomarker of depression that will predict response to treatment before or shortly after starting an antidepressant. Using independent component analysis of resting-state fMRI data, functional connectivity will be assessed separately in three brain networks that we have previously related to mood, anxiety, and executive function. Thirty drug-free patients with depression will be scanned at baseline, at one week, and at eight weeks after treatment with citalopram. Brain network connectivity in the baseline depressed state will be compared to network connectivity in thirty healthy controls using a two-sample t-test. Baseline network connectivity in the depressed subjects will be correlated against measures of mood, anxiety, and cognition to explore relationships between distinct networks and distinct symptoms of depression. Baseline scans of responders and non-responders will be compared using a two-sample t-test to search for patterns of brain network connectivity that can predict treatment response or failure. Finally, paired t-tests, performed separately in responders and non-responders, will compare changes in network connectivity between the baseline scan and the one-week and eight-week scans to determine if early network changes seen at one week can predict subsequent clinical outcome at eight weeks. Meeting the goals of this study will advance our understanding of the brain bases of depression and allow for concrete clinical applications of fMRI in its treatment.

Psychotherapy remains a cornerstone of treatment for many psychiatric disorders, and can be highly highly effective for a portion of patients. Very little, however, is understood about the neurobiological mechanisms of action of psychotherapy, nor are there biological markers for who is likely to respond. For some disorders, such as posttraumatic stress disorder (PTSD), psychotherapy is also the only evidence-based treatment, leaving non-responders with no effective treatment alternative. A lot is known, by contrast, about the neural basis of PTSD. Despite this, there is a large gap between our understanding of the neural basis of psychopathology in PTSD and the mechanisms of therapeutic change, and an even larger gap between those and an ability to use information from neuroimaging studies to guide the development of novel, neurocircuitry-targeting treatments. This latter issue is one, in fact, that plagues neuroimaging studies of psychiatric disorders more generally. Development of such novel treatments is a major goal of the Strategic Plan of the NIMH, and thus the BRAINS RFA, and may bring new hope to the treatment of severe illnesses, such as PTSD. The overall goal of this research program is to apply functional magnetic resonance imaging (fMRI) to elucidate the brain circuitry underlying improvement in response to psychotherapy, and to leverage this knowledge to develop a novel, personalized, neurocircuitrytargeting treatment using transcranial magnetic stimulation (TMS). One potential mechanism of action of psychotherapy is the alteration of patterns of dysfunctional emotional processing. Numerous studies with healthy subjects has delineated the neural circuitry for reacting to and regulating negative emotion, and how it is perturbed in psychopathology. We propose to build on this knowledge and study psychotherapeutic change and its pretreatment predictors by systematically probing emotional reactivity and regulation using fMRI in patients with PTSD before and after treatment with prolonged exposure psychotherapy (PE), versus wait list. Before receiving PE, all patients will undergo mapping of the prefrontal cortex using concurrent TMS and fMRI. Patterns of brain activation induced and modulated by TMS at a variety of prefrontal sites will be compared to those associated with successful PE, thereby forming the basis for a future neuroimaging-guided TMS intervention strategy that is directly informed by an understanding of the neurocircuitry of treatment response. A successful outcome in this study may therefore produce a paradigm shift in the translation of clinical neuroscience to brain circuitbased interventions.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: Clinical data suggest that abnormalities in the regulation of emotional processing contribute to the pathophysiology of generalized anxiety disorder, yet these abnormalities remain poorly understood at the neurobiological level. We recently reported in healthy volunteers that the pregenual anterior cingulate regulates emotional conflict on a trial-by-trial basis by dampening activity in the amygdala. We also showed that this process is specific to the regulation of emotional, compared to non-emotional, conflict. Here we examined whether this form of non-instructed emotion regulation is perturbed in generalized anxiety disorder. Methods: 17 patients and 24 healthy comparison subjects, were studied using functional magnetic resonance imaging while they performed an emotional conflict task, which involved categorizing facial affect while ignoring overlayed affect label words. We compared trial-by-trial changes in conflict regulation using behavioral and neural measures. To read about other projects ongoing at the Lucas Center, please visit http://rsl.stanford.edu/ (Lucas Annual Report and ISMRM 2011 Abstracts)

DESCRIPTION (provided by applicant): This application aims to delineate the neural basis of late life anxiety and depressive disorders. As many as 15% of adults over the age of 60 years in the U.S. suffer from anxiety or depressive disorders. These disorders in late life are disabling, reduce the quality of life, impair cognitive processing and increase morbidity and mortality. Little is known about the neurocircuitry underlying these disorders in older adults, an issue that is further complicated by the neurodegenerative changes that accompany the aging process. Increased characterization of the neural basis of late life mood and anxiety disorders is essential for increasing our understanding of a) the etiology of these disorders; b) their differential diagnosis; c) their relationship to age- related neurodegeneration and cognitive decline; d) vulnerability and resilience factors; e) predictors of treatment response; and also for the f) establishment of the basis for development of rational therapeutics targeting defined neural circuits. We propose to provide this much-needed neurobiological foundation by investigating in patients with late life depression and anxiety innovative fMRI paradigms that we have utilized to identify differential neural substrates of depression and anxiety in young adults that both characterize and distinguish these disorders. To achieve our objective of characterizing late life MDD and GAD at a neural circuit level, we will apply these neuroimaging probes to 160 older adults (>60 years old) falling equally into four groups: GAD only, MDD only, comorbid GAD/MDD and healthy controls, while also examining non- emotional cognitive control processes that parallel emotion regulatory ones, and assessing a range of cognitive functions through neuropsychological testing. Our Specific Aims, based on our preliminary data and considerations regarding age-related cognitive decline, are: Aim 1: To examine if fMRI measures of emotional processing and regulation are associated with different patterns of impaired neurocircuitry in late life GAD versus late life MDD. Aim 2: To examine if neurocircuitry abnormalities in co-morbid late life GAD and MDD are additive. Aim 3: To examine if dysregulation of emotional processing in late life GAD and MDD is due to impaired executive control during cognitive processing.

DESCRIPTION (provided by applicant): Anxiety and mood disorders are highly prevalent, often co-morbid, and when so, are associated with increased morbidity and disability. In particular, anxiety in the context of depression predicts worse outcome with a range of treatments. The commonality of excessive, uncontrollable negative emotion across anxiety and mood disorders suggests a core deficit in emotional reactivity and regulation. We, and others, have delineated a neurobehavioral system, involving the anterior cingulate, amygdala, and lateral prefrontal cortex, that is involved in emotional reactivity and regulation. Both activity ad connectivity within this circuit are perturbed in patients with anxiety and mood disorders, supporting the hypothesis that dysfunction in the handling of emotion lies at the core of these disorders, and that validated tools are now available for objectively assessing this neural system. These findings constitute a robust scientific foundation for novel intervention approaches aimed at improving emotion regulation, which could be delivered over the internet, thereby also increasing availability of effective treatments. We propose to pilot a novel, internet delivered neuroplasticity-based neurobehavioral intervention, which improves emotion regulation by 1) instilling a bias towards positive stimuli, 2) improving resistance to emotional distraction, and 3) enhancing executive functioning more generally (e.g. working memory, task switching, resisting interference), as these are required for successful implementation of emotion regulation (ER). In the R21 phase, thirty medication-free patients with anxious depression (total Ham-D1¿7e16, Ham-D17 anxiety subscale ¿7) will be given 60 days of internet-delivered training. The aim of this phase is to optimize the training and assessment procedures (symptom, behavioral and fMRI), as well as to provide initial evidence for generalization of the training to measures relevant for anxiety and depression. In the R33 phase, sixty medication-free patients with anxious depression will be randomized to receive the 60-day ER neurobehavioral intervention (with adjustments if indicated by the R21) or an active control arm of online tasks that are similarly engaging but provide no emotion regulatory benefits. The aim of this phase is to provide initial evidence supporting the utility of an optimizd version of the neurobehavioral intervention, focusing on effect size estimation and delineation of recruitment and implementation parameters for a large-scale clinical trial. We foresee our internet-delivered, adaptive neurobehavioral training for ER as being applicable for a range of psychiatric disorders, and in particular for mood or anxiety disorders. Successful completion of the proposed study would provide compelling initial evidence for the utility of this novel intervention approach, guided by a neuroscientific understanding of core deficits in anxiety and depression, for a larger and more definitive clinical trial. PUBLIC HEALTH RELEVANCE: Anxiety and mood disorders are highly prevalent, often co-morbid, and when so, are associated with increased morbidity and disability, as well as worse outcome with a range of treatments. Psychosocial treatments, even when effective, are often difficult for patients to obtain - thus, there is a pressing clinical need for development of novel treatment interventions. The long-term objective of the proposed work is to leverage our emerging neuroscientific understanding of anxiety and depression into a highly innovative, novel brain-based neurobehavioral treatment that can augment or form an alternative to the currently limited set of treatments.

DESCRIPTION (provided by applicant): At present, the ability to apply or develop neurocircuitry-based treatments founded on cognitive neuroscience is still extremely limited for two fundamental reasons: 1) conventional neuroimaging studies provide information on correlations between brain and behavior, but not how activity in one brain region directly drives activation or inhibition in another. To understand the causal relationships between different brain regions or networks, it is necessary to exert direct experimental control over specific brain regions and simultaneously image the consequences on other brain regions or networks. We refer to this as a causal circuit map. Consequently, 2) it is unknown which specific neural pathways within these causal circuit maps are abnormal and which are intact in patients, and how particular clinical factors such as trauma exposure impact these brain pathways. It would be of fundamental theoretical and practical importance for implementing a future circuit-targeting neuromodulatory intervention to know, for example, whether stimulation should be directed to intact pathways or to abnormal ones (with a goal of normalizing dysfunction). Without causal circuit mapping, target identification and validation for future neuromodulatory treatments, such as repetitive transcranial magnetic stimulation (rTMS), will remain as trial-and-error guesswork. An additional limitation of prior studies on mood/anxiety-related disorders is that the DSM does not capture the full spectrum of clinically-significant negative affect symptomatology, including the role of trauma in clinical syndromes beyond post-traumatic stress. Our primary focus in this proposal is therefore to delineate for the first time the causal circuit maps relevant for impairments in emotion regulation (ER) and executive function (EF) in a broad range of chronically ill patients with high negative affect symptoms, consistent with the aims of the Research Domain Criteria Project (RDoC). Prior work on high negative affect disorders with correlational imaging has found abnormalities across multiple nodes in several well-defined large-scale neuronal networks. However, unlike these prior correlational studies, we propose to employ a causal circuit mapping neuroimaging approach to achieve an unprecedented level of specificity with regard to which causal brain pathways are intact and which are abnormal. Here we provide this casual map by direct brain activation using non-invasive single pulse excitatory TMS (spTMS), combined with visualization of network effects using concurrent functional magnetic resonance imaging (fMRI). The targets for spTMS/fMRI are cortical regions within well-defined large-scale networks relevant to ER/EF (eight bilateral prefrontal sites as well as one control site), thus systematically linking causal maps to circuit-level models of the illnesses A successful outcome from this study would be directly useful in guiding how and where to target existing long-term neuromodulatory interventions, and lay the groundwork for the development of novel methods.

DESCRIPTION (provided by applicant): Electrical, chemical, and genetic manipulation of brain circuitry in non-human animals has led to important advances in our understanding of how learned fear is acquired, how it is extinguished (lessened by experience with contradictory evidence), and how in some cases fear memories persist in eliciting stress reactions despite evidence that the feared aversive event will not recur. In the case of posttraumatic stress disorder (PTSD) in humans, evidence suggests that fear memories persist and the location of brain abnormalities underlying this persistence are consistent with the evidence for the neurobiological substrates of fear memory extinction retention gathered from non-human animal studies. By manipulating this same circuitry in humans in the context of fear extinction, it may be possible to augment the lessening of stress reactions to learned fear cues. The proposed study seeks to determine the parameters best suited for this augmentation in healthy participants using repetitive transcranial magnetic stimulation (rTMS). By testing behavioral and psychophysiological responses to learned fear cues before and after extinction in conjunction with applying rTMS to multiple brain targets, the effectiveness of each target in augmenting fear memory extinction will be evaluated. Applying rTMS interleaved with neuroimaging (functional magnetic resonance imaging) to these targeted brain areas will yield additional evidence of how induced plasticity in key brain circuits implicated in the task and in PTSD pathophysiology may relate to fear learning and extinction. Multiple targets will be evaluated this way in healthy participants before one or more can be selected for testing in patients diagnosed with PTSD. The effectiveness of rTMS to influence behavioral and psychophysiological responding to learned fear cues will thus be explored in healthy populations as a function of induced plasticity mechanisms measured in this context for the first time combining TMS/fMRI methods. The evidence gathered from these measures will provide a novel framework for evaluating neurobiological improvements in PTSD and may also support particular brain regions for targeting in a subsequent rTMS treatment.

? DESCRIPTION (provided by applicant): Women diagnosed with breast cancer are choosing bilateral mastectomy (BLM) at increasing rates, currently 14.3%, and 33% of those under 40. This is happening despite evidence that there is no survival benefit from BLM, along with surgical complications and other serious medical and personal costs, compared with more conservative approaches. Women's anxiety about recurrence is critical to this decision, so their choice may in large part reflect the way they experience and regulate affect. To understand the neurobiological and affective determinants of the choice of BLM, and thereby identify future opportunities for new interventions, we propose to examine the relationship between affect reactivity and regulation and women's decisions regarding BLM after initial diagnosis of breast cancer. We will also examine the impact of affect management and treatment decisions on subsequent psychosocial functioning. The study will involve recruiting a sample of 150 women recently diagnosed with breast cancer after their decision about treatment (75 who have elected BLM and 75 demographically and medically similar women who have decided not to have BLM), as well as a matched control group of 50 women without breast cancer. Affective reactivity to negative non-cancer and cancer- related stimuli will be studied using functional magnetic resonance imagining (fMRI). Likewise, affective regulation will be assessed with fMRI probes of both explicit (i.e. conscious, deliberate) and implicit (i.e. nonconscious, automatic) regulation o negative non-cancer and cancer-related stimuli. Psychosocial functioning will be assessed using self-report measures of anxiety, depression, well-being and functional status at 6, 12, and 18 months post-decision. Informational (e.g. awareness of influential people who have undergone BLM), and demographic variables (age, race, SES) will also be assessed. A physiological stress response measure, diurnal salivary cortisol slope, will be obtained at baseline and all follow-ups. This measure has been shown be associated with expression of negative affect, and to predict breast cancer progression. Our Specific Aims are to: 1) Examine affect reactivity and regulation among women with a recent diagnosis of breast cancer in comparison to healthy controls; 2) Relate affect reactivity and regulation to choice of BLM; and 3) Assess long term functional consequences of BLM decision and affect reactivity and regulation. This study will provide an empirical basis for better assisting patients in making difficult but important choices regarding breast cancer treatment alternatives.

SUMMARY/ABSTRACT    Mental  illnesses  are  the  largest  source  of  healthcare  utilization  costs  in  the  US,  and  the  costliest  of  non-­ communicable diseases worldwide ? estimated to result in $6 Trillion in annual societal burden by 2030. The  way  in  which  we  have  defined  psychiatric  diagnoses  (i.e.  based  only  on  symptom  clusters)  and  identified  treatments  (i.e.  capitalizing  on  serendipity),  has  failed  to  substantially  mitigate  the  disabling  burden  of  these  diseases, which typically appear early in life and persist. Not surprisingly, individual psychiatric diagnoses are  highly  clinically  and  biologically  heterogeneous,  with  as  much  or  greater  variability  within  a  diagnosis  as  between  diagnoses.  The  number  of  mechanistically  distinct  psychiatric  drug  targets  has  also  not  grown  in  decades,  and  typically  only  half  of  patients  respond  well  in  clinical  trials.  Public  stigma  towards  psychiatric  disorders  remains  palpable,  as  lay  understanding  of  the  brain  bases  of  these  conditions  contrasts  with  the  growing  excitement  amongst  scientists  for  the  potential  of  grounding  diagnosis  and  treatment  directly  in  neurobiology. Neuroimaging, as the dominant tool in human neuroscience, however, has been used largely for  comparing  these  arbitrarily-­defined  diagnoses  against  healthy  individuals  not  for  robustly  characterizing  individual patients in objective biological terms. Imaging is also a purely observational method, and thus cannot  by itself provide the causal understanding of circuitry that is necessary for transitioning from a descriptive to a  circuit-­based  mechanistic  understanding  of  mental  illness  that  can  directly  guide  novel  interventions.  Here,  I  propose  a  new  diagnostic  and  treatment  development  framework  that  transcends  the  arbitrariness  and  heterogeneity  of  traditional  diagnoses,  the  limitations  of  group-­level  imaging  analyses  and  current  trial-­and-­ error  approaches  to  treatment  planning.  Rather,  this  ?Circuits-­First?  platform  focuses  on  understanding  causality in the brain circuits of individual patients as a means for personalized diagnosis and treatment using  individually-­tailored plasticity-­inducing neurostimulation, establishing direct linkage between circuits and clinical  outcome.  Successful  implementation  of  this  ?Circuits-­First?  approach  will  establish  a  platform  for  rapid  translation  to  other  psychiatric  disorders,  and  beyond  to  specific  neurological  disorders  (e.g.  stroke,  Parkinson?s) where circuit perturbations are prominent. Importantly, despite its novelty, my approach will create  a readily scalable platform that, with simple modifications, can have the potential to transform clinical practice  in  the  near  term.  This  is  facilitated  by  the  use  of  broadly-­applicable,  already  FDA-­approved  tools  (e.g.  transcranial  magnetic  stimulation  (TMS)  and  electroencephalography  (EEG)),  and  the  fact  that  it  can  be  performed  in  the  office-­based  settings  of  the  clinical  practitioner,  thus  not  restricted  to  specialized  research  labs. 

SUMMARY Post-traumatic stress disorder (PTSD) is a chronic and disabling disorder with currently limited effective treatments. Its severity and functional impairment is compounded by frequently comorbid alcohol use disorder (AUD), which also has limited effective treatments in isolation or in combination with PTSD. Alcohol use can be considered within the broader framework of emotion dysregulation in PTSD, as it is often pursued initially as an (often maladaptive) way to cope with distressing emotions. When alcohol use is prolonged and excessive, alcohol dependence can ensue, manifesting in substantially greater functional impairment and deficiency of prefrontal function and emotion regulation. Together, these lines of evidence suggest that: a) reduced ability to regulate excessive negative affect presents a primary vulnerability factor for alcohol use in PTSD+AUD; and b) individual differences in prefrontal-amygdala neural circuit interactions may be important predictors and/or mechanistic determinants of outcomes for PTSD + AUD treatments. As such, there is a pressing clinical need to advance the treatment of PTSD+AUD, which is most efficiently accomplished by understanding who responds best to a given treatment and what are the mechanisms by which that treatment works. Here we propose to answer these questions using a sophisticated moderation/mediation framework and multi-modal human brain circuit functional assessments in the context of a randomized clinical trial comparing the treatment of PTSD+AUD with topiramate versus placebo. Evidence exists for the utility of topiramate, which facilitates inhibitory ?-amino-butyric acid (GABA) signaling and antagonizes excitatory glutamatergric signaling, in the treatment of AUD, with initial evidence of utility for PTSD+AUD, making it a promising target for neuromechanistic study. Therefore, at the heart of our approach is a thorough cognitive neuroscience assessment of emotional reactivity and regulation to general negative stimuli and reactivity to alcohol cues more specifically (using functional magnetic resonance imaging (fMRI)). This is complemented by a cutting- edge mapping of the same brain circuits at the neurophysiological level using concurrent transcranial magnetic stimulation and EEG (TMS/EEG). Given the pharmacological action of topiramate, concurrent TMS/EEG is an ideal tool for direct interrogation of its neurophysiological actions. This is because TMS/EEG indexes distinct excitation-related and inhibition-related neurophysiological responses to brain circuit-targeted targeted neurostimulation, with EEG responses source-localized to the specific cortical structures investigated by the fMRI tasks above and investigated at a neuronal temporal scale.

SUMMARY/ABSTRACT    Mental  illnesses  are  the  largest  source  of  healthcare  utilization  costs  in  the  US,  and  the  costliest  of  non-­ communicable diseases worldwide ? estimated to result in $6 Trillion in annual societal burden by 2030. The  way  in  which  we  have  defined  psychiatric  diagnoses  (i.e.  based  only  on  symptom  clusters)  and  identified  treatments  (i.e.  capitalizing  on  serendipity),  has  failed  to  substantially  mitigate  the  disabling  burden  of  these  diseases, which typically appear early in life and persist. Not surprisingly, individual psychiatric diagnoses are  highly  clinically  and  biologically  heterogeneous,  with  as  much  or  greater  variability  within  a  diagnosis  as  between  diagnoses.  The  number  of  mechanistically  distinct  psychiatric  drug  targets  has  also  not  grown  in  decades,  and  typically  only  half  of  patients  respond  well  in  clinical  trials.  Public  stigma  towards  psychiatric  disorders  remains  palpable,  as  lay  understanding  of  the  brain  bases  of  these  conditions  contrasts  with  the  growing  excitement  amongst  scientists  for  the  potential  of  grounding  diagnosis  and  treatment  directly  in  neurobiology. Neuroimaging, as the dominant tool in human neuroscience, however, has been used largely for  comparing  these  arbitrarily-­defined  diagnoses  against  healthy  individuals  not  for  robustly  characterizing  individual patients in objective biological terms. Imaging is also a purely observational method, and thus cannot  by itself provide the causal understanding of circuitry that is necessary for transitioning from a descriptive to a  circuit-­based  mechanistic  understanding  of  mental  illness  that  can  directly  guide  novel  interventions.  Here,  I  propose  a  new  diagnostic  and  treatment  development  framework  that  transcends  the  arbitrariness  and  heterogeneity  of  traditional  diagnoses,  the  limitations  of  group-­level  imaging  analyses  and  current  trial-­and-­ error  approaches  to  treatment  planning.  Rather,  this  ?Circuits-­First?  platform  focuses  on  understanding  causality in the brain circuits of individual patients as a means for personalized diagnosis and treatment using  individually-­tailored plasticity-­inducing neurostimulation, establishing direct linkage between circuits and clinical  outcome.  Successful  implementation  of  this  ?Circuits-­First?  approach  will  establish  a  platform  for  rapid  translation  to  other  psychiatric  disorders,  and  beyond  to  specific  neurological  disorders  (e.g.  stroke,  Parkinson?s) where circuit perturbations are prominent. Importantly, despite its novelty, my approach will create  a readily scalable platform that, with simple modifications, can have the potential to transform clinical practice  in  the  near  term.  This  is  facilitated  by  the  use  of  broadly-­applicable,  already  FDA-­approved  tools  (e.g.  transcranial  magnetic  stimulation  (TMS)  and  electroencephalography  (EEG)),  and  the  fact  that  it  can  be  performed  in  the  office-­based  settings  of  the  clinical  practitioner,  thus  not  restricted  to  specialized  research  labs. 

SUMMARY/ABSTRACT The overarching aim of Alto Neuroscience is to advance brain-based biomarkers for psychiatric disorders in order to both optimize treatment pathways and drive the development of novel pharmacological and non- pharmacological interventions. Alto does this by developing and applying sophisticated machine learning computational models to electroencephalography (EEG) data collected at scale in real-world clinical treatment contexts. Specifically, in this direct-to-phase II SBIR proposal we will refine, and then independently validate, two EEG-based candidate biomarkers we have identified for stratifying patients with depression in a manner that both factors biological heterogeneity and informs treatment response. One of our biomarkers was derived in a ?top-down? (i.e. supervised) manner by trying to directly predict treatment outcome, while the other biomarker presents a complimentary ?bottom-up? (i.e. unsupervised) approach that begins by first identifying the most biologically homogeneous subset of patients and then testing the treatment relevance of the subtyping. Together, these findings represent very robust individual patient-level treatment-relevant EEG biomarkers, and in both cases, help define a critically-important objective approach to prospectively identifying and treating treatment- resistant depressed patients. A successful outcome of the proposed work would yield the first FDA-cleared biomarkers for stratifying psychiatric conditions. It would also provide a basis for targeted development of pharmacological and non-pharmacological interventions based on the EEG biomarkers. Both outcomes hold substantial commercial value and exciting potential for transforming psychiatry.