Deep Brain Stimulation for Pediatric Dystonia: Clinicians’ Perspectives on the Most Pressing Ethical Challenges

Deep brain stimulation (DBS) is a Food and Drug Administration (FDA)-approved treatment for adults with refractory movement disorders such as Parkinson’s disease, essential tremor, offered under FDA-humanitarian device exemptions (HDEs) for adults with refractory dystonia and obsessive compulsive disorder (OCD) [1‒5]. The use of DBS in children (≤18 years old) has received little attention but is quickly increasing [3‒7] and shows great promise [8‒11]. Evidence of its efficacy led the FDA [12] to allow clinicians to offer DBS under a HDE to refractory pediatric patients with dystonia over 7 years of age, making this movement disorder the most common indication for pediatric DBS (pDBS).

pDBS has been shown to be effective particularly for certain etiologies of dystonia that involve hereditary transmission (“primary”) dystonia [6]; however, risk-benefit ratios are less clear for acquired (or “secondary”) dystonia (SD) resulting from neurological disease or injury (e.g., cerebral palsy) or with no known cause [13‒16]. One exception is tardive dystonia, for which there are several reports of robust improvement with long-term benefit [17, 18]. Among patients with PD, those with a pathological mutation in DYT1 (DYT1+) appear to be more likely to experience an improvement in disability scores compared to patients who are DYT1− [8]. A review of long-term management of DBS in dystonia [19] reports that potential complications may occur, primarily stimulation-related (e.g., speech abnormalities, paresthesias, perioral tingling, gait and postural disturbances) and hardware-related (skin infection/erosion, implantable pulse generator malfunction/hematoma/infection, electrode damage, lead fracture/misplacement, or extension wire failure). Evidence [19, 20] suggests that certain hardware-related complications, including those caused by lead fractures (more frequent in dystonia patients than in other movement disorder patients), may be reduced by repositioning connectors. However, efforts to reduce other complications, such as infection (via the use of intrawound vancomycin powder), have been more difficult to evaluate due to low baseline infection rates.

The high degree of inter-patient variability in etiology and outcomes [6, 8] and the small numbers of pediatric patients receiving DBS for dystonia contribute to persistent uncertainties about DBS outcomes in pediatric populations. However, a recent ethical analysis of risk/benefit tradeoffs suggests [21] that offering pDBS as a countermeasure to this enduring disability is ethically justified despite uncertainty about outcomes, given the scope of need: there are currently more than 200,000 dystonia cases with childhood onset [22]. These individuals can experience significant pain and impairment, and many have symptoms that are refractory and can become severe and potentially life threatening [4]. Many treatments for dystonia in pediatric patients are ineffective at alleviating symptoms. Pharmacological options remain a first-line treatment option, followed by botulinum toxin injections for focal elements of dystonia and intrathecal (or even intraventricular) baclofen. However, dystonia symptoms are either partial or nonresponsive to these treatments, often resulting in prolonged physical impairments.

To date, there has been little systematic research into ethical issues related to the use of pDBS for dystonia, including a dearth of theoretical pediatric neuroethics research [23‒25], though empirical neuroethics research focused on pDBS is growing [21, 26]. The use of pDBS to treat both primary dystonia and SD requires a high level of ethical scrutiny, given that children and adolescents with dystonia constitute a complex and vulnerable population with often limited capacity (including intellectual maturity and neurocognitive capacity) to autonomously consent to treatment [27, 28]. This paper is one of the first empirical neuroethics studies to identify pressing ethical issues in DBS applied to pediatric populations. Here, we share perspectives of clinicians with expert insights into relevant practical and ethical challenges involved in caring for pediatric patients who are considering or already receiving DBS treatment for dystonia. We contextualize these findings within the existing neuroethics literature and discuss potential responses to these concerns.

Using in-depth, semi-structured interviews, we explored perspectives and experiences of clinicians working in active DBS programs involved in treating children and adolescents with refractory dystonia. Our aim was to identify decisional factors and ethical issues related to DBS for childhood dystonia. An interview guide (see online suppl. materials; for all online suppl. material, see https://doi.org/10.1159/000530694) was developed based on issues raised in the clinical and ethics literature and through discussions with DBS and movement disorder experts. An initial draft of the guide was reviewed by an advisory team and piloted with a neurologist specializing in movement disorders, resulting in minor clarifications in wording. Questions explored a variety of potential ethical concerns, including informational and decisional needs for offering DBS to a pediatric population, issues related to consent and decisional roles and capacity, decision-making in contexts of uncertainty, managing patient and caregiver understandings and expectations, public perspectives and social implications, legal regulations and oversight, and financial/insurance and access issues. The study was reviewed and approved by the Baylor College of Medicine Institutional Review Board (Approval# H-45996), which also waived a requirement for written consent for this project; thus, participants provided verbal consent.

Potential clinician participants were identified through web searches of established DBS centers specializing in movement disorders, literature searches for authors writing about DBS in dystonia, and referrals from clinicians on our advisory panel. Participants included neurologists and neurosurgeons with experience with pediatric populations, as well as other healthcare providers with relevant insights into potential ethical and quality-of-life considerations for pDBS for dystonia (Table 1). Participants were recruited via email between January 2021 and April 2021 with the goal of sampling movement disorder specialists from different regions in the USA (n = 25) and in the UK, France, and Canada (n = 4) with well-established pDBS centers. Interviews were conducted via phone or videoconference by two members of the researcher team (LT & KM) trained in qualitative interviewing and had an average duration of 70 min.

Interviews were audio-recorded, transcribed verbatim, and analyzed using MAXQDA software [29]. Led by KK-Q, a qualitative method expert and medical anthropologist, team members (LT, KM, KK-Q) developed a codebook to identify thematic patterns in clinicians’ responses about ethical issues and concerns. Each interview was coded by merging work from two separate coders. Thematic content analysis [30] was used to identify themes [31] by progressively abstracting relevant quotes. These abstractions were validated by at least one other member of the research team before calculating thematic frequencies to characterize clinicians’ responses. Frequencies and percentages reflect only reported information and are not intended to suggest any level of statistical significance.

A total of 56 clinicians working with pediatric patients with movement disorders and who either specialize in pediatrics or have substantial experience with pediatric patients were contacted; 29 participated (response rate = 52%) (Table 1). Thematic analysis revealed four pressing ethical concerns (Table 1): (1) uncertainty about risks and benefits of pDBS (73%) that pose a challenge to informed decision-making; (2) ethically navigating decision-making roles (50%), including how best to integrate perspectives from diverse stakeholders (patient, caregiver, clinician) and how to manage surrogate decisions on behalf of pediatric patients with limited capacity to make autonomous decisions; (3) effects of information scarcity on informed consent and decision quality (46%) in the context of patient and caregivers’ expectations for treatment; and (4) narrow regulatory status and access (7/29; 24%) such as the lack of FDA-approved indications that contribute to decision-making uncertainty and liability and potentially limit access to DBS among patients who may benefit from it.

These themes are illustrated in Figure 1 in the context of our code list, which we used to identify key topics and concerns related to pDBS (see Data Analysis above). In this figure representing code relations, closer proximity indicates more frequent “co-occurrences” of given codes (# of times applied to same text segment). This illustration offers a preliminary glance into conceptual relations that emerged from our data; however, a closer, qualitative examination of text segments was used to identify the themes listed in Table 2. As such, some of the code clusters that appear in Figure 1 did not ultimately qualify as themes, defined as patterns of shared meaning united by a central concept, idea, or narrative [31]. We identified our themes both inductively, following our familiarization of the data, and deductively, drawing on understandings drawn from prior research or theory. Using our own first principles, we set a threshold for a “salient” theme as one where concerns were raised by at least 25% of respondents. Thus, while some of the codes and findings cluster (e.g., around personality and identity, authenticity, etc.), they did not represent shared concerns or themes relevant to this paper. All relevant, salient themes are discussed below, with additional quotations in Tables 3 and 4.

Nearly three quarters (72%) of respondents shared a concern that the risks and uncertainties associated with DBS treatment among pediatric populations pose an ethical challenge to informed decision-making. Clinicians said that because DBS is a novel treatment not yet widely used among children and adolescents, there is a consequent lack of definitive evidence concerning outcomes or insights into ideal approaches to program stimulation parameters in pediatric population (Table 2). The high degree of variation within the small population sample of pediatric dystonia patients receiving DBS exacerbates these uncertainties. As one clinician said, “We don’t have straightforward patients” (05). Other respondents highlighted that there is so far insufficient evidence to assume that the benefits of DBS seen among adults may be extrapolated to pediatric populations. While benefits “do seem to last” (14) in many pediatric patients, long-term effects and efficacy are difficult to gauge, said clinicians. One clinician (25) pointed out that “We don’t know whether stimulation can have cognitive and emotional changes in the long run,” making it difficult to accurately weigh expected benefits against potential risks.

These uncertainties make it difficult to communicate to families whether DBS may be an appropriate treatment for pediatric patients. Clinicians said they find it challenging to mitigate conversations with families about risks versus benefits in the absence of extensive outcome data. One clinician shared, “It’s not fully understood how it really works, but we know it does help. Without knowing exact mechanism and what your outcome is, (it’s) harder to (know whether it is the right choice)” (10).

This inability to clearly delineate risk/benefit ratios further complicates clinicians’ ability to ensure informed consent and decision quality. Many respondents (52%) raised this as an ethical issue impacting families’ ability to provide “real, realistic consent” (14). One clinician (26) said, “Because we don’t know the long-term efficacy, we can’t really communicate clearly this with our population.” Another (13) highlighted that families may not fully understand that “all DBS in children is actually a research project,” that a physician’s role is to make its investigational nature clear, and that a number of factors – some known and some unknown yet – can impact outcomes of DBS in pediatric patients.

For example, one major consideration when assessing risks vs. benefits is whether to undergo DBS early or to wait until a patient is older. One clinician (017) said, “I think the ethical issues would be what is the lower age limits that we feel comfortable implanting patients with? The younger these patients get, the more, it gets a little ethically dicey for it.” This same respondent highlighted potential “physiological reasons to hold off… to wait until the skull is fully or nearly fully formed, for instance.” There is often a shared concern between clinicians and families “that we’re not rushing to surgery,” said one clinician (11), if a child has “some mild limitations there that can be resolved with other therapeutic mechanisms.” On the other hand, other clinicians cautioned “not to wait too long, because (it could be) deleterious” (15). One respondent (06) stated, “I think families… if they hear that risk is low and that there’s potential for benefit, I think most of the time people are eager to do that (consent to pDBS).”

Clinicians highlighted an ethical concern that consent under these conditions is by necessity based less on objective considerations of likely risks and benefits (as they are unknown) than on subjective criteria, such as perceived urgency to find a solution, emotional factors, or trust in physicians and the clinical team. They pointed out that in such a decision-making context, it becomes even more ethically imperative for clinical teams to help manage patients’ and families’ expectations. As one respondent (25) highlighted, “We’re consigning a child with DBS to a different class of childhood, in a lot of ways. They’re not going to be in the weight room bench pressing. They’re not going to wear strapless gowns. They’re not going to be going off with friends on a carefree weekend where parents just check in by cell phone.” Further, some clinicians feel responsible for conveying to families that “there’s going to be increased burden of care here, because at least early on after the surgery, we’re going to be having lots of trips,” said one clinician (28). He continued, “Then the cost (including) the device, the surgery, everything, all in, $100,000 or so, but then every 4 years you have to get it (the battery) replaced… What are the costs of these things, and what is the long-term commitment? I make sure that they know that this is something that has some added implications compared to, say, taking a daily medication.”

Over half (52%) of respondents raised significant ethical concerns about who should provide consent in order to move forward with DBS, considering both the young age of pediatric patients and the invasiveness of therapy. One clinician (12) characterized “the number one issue” as “operating on a child… who’s technically not the age of consent.” Another (16) asked “Can the patient consent, do the parents assent?” and explained, “That kind of complex ‘approval’ to move forward is always a challenge and is ethically powerful.”

Many clinicians highlighted the fact that DBS is “a major life altering brain surgery” (01) requiring continued postoperative care. Not all pediatric patients will share a capacity to understand the nature and potential implications of DBS therapy. Clinicians said that such cases raise ethical concerns about whether other family members (most often parents) should be allowed to or responsible for offering consent on a pediatric patient’s behalf. One respondent (02) pointed out that “These are kids that already have tons and tons of dependencies and… they really can’t consent entirely independently, because they’re [already] dependent on everyone around them.” While many clinicians explicitly highlighted the importance of autonomy in decision-making, they also acknowledged that the conditions for autonomous and informed decision-making in the context of pDBS do not fully exist.

Respondents shared illustrative examples of scenarios in which pediatric patients and their families might disagree about whether to proceed with DBS, citing them as particularly ethically challenging scenarios. Clinicians expressed ethical reservations about whether to intervene or to remain neutral, and how to manage diverging perspectives. In some cases, clinicians supported allowing their perspective to inform their recommendations to patients and family members. As one respondent (20) described, “All of those personal biases (are) going to play in to what I’m going to propose to the family and how I’m going to propose it.” Other clinicians, meanwhile, advocated taking a more neutral approach and reflecting upon “how (to) be unbiased… when giving all of the options to the family, to decide what they want to do?” (02).

Some clinicians suggested that the ethical challenge of “deciding who should decide” may be mitigated by engaging multiple perspectives, sometimes even inviting perspectives outside of the triad among physician, pediatric patient, and family member. One clinician (14) said “There’s also the ethical issue [of] am I, as a physician and researcher who studies DBS, do I have any undue conflict of interest on myself making this recommendation?” Another respondent (16) pointed out, “When there is that kind of unknown, an ethics consult or ethics team can be helpful. We (also) try to have a multidisciplinary review of our pediatric patients to try to improve the rigor of our decision-making.”

Over a quarter (27%) of respondents expressed concerns about the regulatory status of pDBS, the lack of medical-legal infrastructure to support the needs of pDBS patients, and a dearth of legal protections for clinicians offering DBS in patients’ best clinical interests. As one clinician (19) poignantly stated, “I think the most pressing ethical issue regarding pDBS for dystonia is the failure of our healthcare system to support it.” This respondent explained that his clinical team performed “a year and a half’s worth of operations that didn’t get paid for” because “all of our dystonia DBS insurance claims were denied.” While DBS for dystonia is covered under a HDE, certain types of dystonia are considered to be “off-label.” A number of clinicians raised this as a critical ethical issue, sharing comments like, “The ethics around primary dystonia, because of FDA approval though, are a bit less than perhaps (for) an off-label indication (like) secondary dystonia. Off-label, the ethics get a little bit larger” (16). Nevertheless, some SD patients respond while others do not. One clinician (27) said that, despite this uncertainty, “the best (treatment option) for secondary [dystonia) is off label at this point, at least in the United States.”

Further, some raised ethical concerns about how current regulations deny coverage for essential medical supplies associated with treatments offered under an HDE. However, this is not currently the case. One clinician (19) explained, “Rechargeable batteries are not included in the humanitarian device exemption…. (so they’re) not approved for the patients who actually need rechargeable batteries, like obsessive compulsive disorder and dystonia where patients typically use more energy and need more frequent battery changes. It’s ridiculous that those patients who need it most are the ones who can’t get it paid for.” Some clinicians expressed uncertainty and even exasperation over who should be expected to pay for continued care. The respondent above (19) continued, “Who’s fighting with the insurance companies? Is it your billing people? Is it you? Is it the parents or is it like everybody?”

Clinicians point out that not only is it problematic that the specific contingencies of offering pDBS under an HDE result in lack of coverage for certain cases where DBS treatment and follow-up care would be clinically beneficial to patients, but clinicians also feel they “risk it for these kids,” as one clinician (02) put it. He continued, “The most pressing issue is the fact that we are going in unprotected. There’s no clear indication. The FDA hasn’t stamped it. From a medical bureaucracy point of view that involves the medical legal system (and) insurance system, I don’t have permission to do any of this, (I’m) always out on a limb.”

Clinicians said that their potential liability is further exacerbated by a lack of guidelines and evidence-based best practices to inform their treatment decisions. One clinician (24) said, “Like how do you program people? There are no guidelines. Everybody does what they learned in training and kind of go off of what they’re comfortable, but I don’t think anybody really knows what’s the ideal way of programming kids.” Another (22) said, “I spend a lot more of my time these days working on trying to figure out how to track these smaller diseases like dystonia, Tourette, OCD (and to) create registries.” This clinician pointed out that while “the field has changed to a field of precision medicine,” the current regulatory system governing DBS treatment is “still operating (as it was) 20 or 40 years ago. We need to have a system that operates and serves the needs of now.”

This systematic inquiry offers empirical support for a number of ethical issues previously raised in the literature on pDBS and post-implant care [21, 27, 28]. Specifically, clinicians’ primary concerns center around enduring uncertainty about risks and benefits of pDBS, due to small population sizes and significant heterogeneity in responses to pDBS. Further, while there is evidence that quality of life is significantly improved for some patients following DBS, longitudinal insights into patient outcomes are lacking [32]. Uncertainties about clinical and other factors impacting pDBS outcomes can compromise informed, quality decision-making, leading clinicians in some cases to lean more heavily on clinical gestalt, and leaving patients and caregivers with little choice but to consider subjective factors (e.g., perceived urgency; hope and optimism about benefits; emotional factors) rather than objective clinical probabilities when making decisions about whether to consent to DBS [33]. Further, decision-making with scarce information complexifies an already complicated decisional dynamic with no clear answer as to whose decision(s) should take precedent. When all parties have limited insights about risks and benefits, clinicians are faced with the challenge of navigating and guiding sometimes divergent perspectives among family members, patients, and/or the clinical team, without any strong compass to point toward a most ethical and effective way, one that ensures patient autonomy as well as clinical benefit.

Decision-making under conditions of extreme uncertainty can trigger certain cognitive biases in decision-making. As we elaborate elsewhere, families are often understandably desperate to alleviate the significant discomfort or pain of their children [21]. As a result, they may be willing to assume a greater amount of risk when considering potential treatments. This may especially be the case where patients and caregivers have tried other treatment options without success. While risk-taking in the context of information deficits and limited alternatives (i.e., “no choice”) may indeed be rational, the circumstances of uncertainty can elicit certain cognitive biases that may elicit less rational forms of decision-making. For example, families may experience unrealistic optimism, a common phenomenon in medicine, characterized by a desire for a certain outcome that leads individuals to overestimate the probability of that desired outcome [34]. Further, the perceived need to act quickly (to alleviate enduring pain or discomfort) may elicit additional biases such as overconfidence effects (placing greater confidence in one’s own judgments than in objective estimates) or illusory control (the belief that one has more control of an outcome than one actually does) [35]. These biases may influence decision-makers to consent to DBS even where promises of certain benefits are lacking. On the other hand, other cognitive biases may have the opposite effect, leading decision-makers to lean away from DBS when it might, in fact, be beneficial. Caregivers, as surrogate decision-makers, are likely to experience significant pressure to make the “right” decision, given its far-reaching impacts on a pediatric patients’ future as well as capacity to self-determine its trajectory [36]. For example, ambiguity aversion (preferring known risks to unknown risks) or loss aversion (the tendency to weigh losses as heavier than gains of equal or greater magnitude) may influence decisions to decline. More research is needed to better understand how conditions of extreme uncertainty regarding risks and benefits impact decision-making and decision quality surrounding pDBS.

A greater understanding of these cognitive biases in decision-making may help clinicians better navigate the dynamics of shared decision-making. This is significant, because one of the key messages conveyed by participants in this study is that many clinicians feel uncertain and concerned about their expected role in decision-making. If a clinician believes a child could benefit but patients or families are not convinced or have yet to consent, clinicians may wonder: is it their role to persuade or nudge patients and families into what clinicians perceive to be an optimal clinical decision? Similarly, if a clinician perceives that emotional or other subjective factors, e.g., a patient’s or parent’s fear, feature prominently in a patient’s or caregiver’s decision-making, how should clinicians most responsibly proceed? An emerging literature on the ethics of nudging [37, 38] suggests that it may be ethically acceptable to nudge patient or caregiver decision-making in a direction that aligns with the most probable clinical benefits and with a patients’ stated values. Assuming these (patient benefits and values) are not at odds, clinicians may be warranted to assume a larger decision management role in shared decision-making about pDBS, nudging patients and caregivers toward the most benefits- and values-aligned decision. However, this approach places great responsibility on clinicians. It also does not take into account that clinicians may have their own biases and incentives as active members of the DBS research community. As a few clinicians from this study pointed out, an ethically responsible approach may be to engage other members of the team in shared decision-making to ensure a balance of perspectives. What is usually conceived of in shared decision-making as a triad of patients-caregivers-clinicians may be more appropriately conceptualized as patients-caregivers-clinical team, both to increase diversity of perspective and to avoid undue responsibility among clinicians for managing decisional dynamics.

Clinicians highlighted that decisional dynamics surrounding pDBS are further complicated by a shared perception that clinicians are engaging in complex decision-making without structural or legal support from the broader medico-legal system. Some clinicians feel that their decisions to offer pDBS are in some cases undermined by systemic factors including a lack of clear regulatory status regarding DBS for specific off-label conditions (e.g., acquired dystonia) for which pDBS may in some (but not all) cases be effective. Paradoxically, insurance companies, following the FDA’s HDE guidelines [12], require greater evidence of widespread benefits (i.e., achieving on-label status) before offering coverage for treatment of such disorders; but in the meantime, generating more evidence is impeded by the high, uncovered costs associated with device, surgical procedure, and continued care (including battery replacement), as well as the lack of systematic clinical trials. When offering DBS, clinicians must therefore consider not only potential clinical risks for a patient but also the significant potential financial risks for families and the negative impacts such stress can have on patient outcomes [39, 40]. While clinicians are finding creative ways to ensure financing for patients in need of DBS who are without the means to pay for treatment [41], these strategies are not likely to be sustainable in the long term. What may be needed is to reconsider, from a regulatory perspective, how much evidence is “enough” in order for pDBS to receive approved labeling for the full range of disorders for which clinicians believe it may provide clinical benefits. Given that DBS has already received HDE clearance for certain disorders for which evidence of efficacy is still accumulating, broadening this designation for other disorders (e.g., OCD and other disorders for which DBS shows significant promise in both adult and pediatric populations) may simultaneously enhance patients’ access to treatment as well as reduce liability concerns among clinicians operating in good faith to alleviate patients’ suffering.

In a previous paper [21], we assessed risks and benefits of offering DBS for dystonia and outlined a number of ethical issues for which our current findings provide empirical evidence. As discussed above, many of these concerns, including those related to determinations of candidacy and the development of patient-centered decision support, revolve around the enduring uncertainties and unknowns of pDBS impacts. This fundamental challenge is being addressed via an expansion of registries to document and share outcome data related to pDBS, both for dystonia and for other pediatric conditions, such as the pediatric international deep brain stimulation registry project (PEDiDBS) [42], the German registry of pDBS in patients with childhood onset dystonia (GEPESTIM) [10], and the CHILD-DBS database [43]. These databases encourage standardization of datasets to facilitate comparability and analysis of a larger number of patients both nationally and internationally. The goal of this research is knowledge gain for clinical benefit, including identification of optimal brain targets for each patient based on individual symptom profiles and stimulation parameters for each brain target or symptom, as well as collection of important safety data critical for regulatory agency approval. As such, outcome data are selectively identified and collected to align with variables potentially necessary for future HDE approval by regulatory agencies in different countries and regions [44]. Converging regulatory and clinical criteria to guide clinical discovery in this way may ultimately lead to safer and more accessible care for patients who could potentially benefit from pDBS.

A second and more immediate way to address uncertainty is to support patient-centered decision-making through the use of decision aids (DAs) for pDBS. Our team is actively engaged in developing such a DA for pediatric patients with dystonia considering DBS treatment. The views reported here represent one among a broader, diverse set of stakeholder perspectives, including patients’ and caregivers’, that provide formative insights into the range of informational and decisional support needs to ensure quality unbiased decision-making in the pDBS setting. An additional function of such a DA is to help decision-makers reflect upon and communicate their values and treatment goals to others (e.g., clinicians, family members) to help ensure their decisions align with treatment goals [45].

While DAs are most often considered to be patient- and family-facing, they may serve a supplementary function of clarifying for all decision-makers – including clinicians – the range of information and resources available to integrate into decisions. Such a tool may help concretize informational assets (knowns) and limitations (unknowns) to consider within the context of patient/family values, help ensure transparency, and reduce bias in decision-making among all parties involved.

This paper provides empirical support that clinicians are primarily concerned about ethical limitations of making difficult decisions in the absence of informational, regulatory, and financial supports. These concerns will persist in the absence of greater knowledge about risks, benefits, and outcomes of DBS for pediatric conditions. We highlight two solutions already underway, including supported decision-making that acknowledges diverse stakeholder perspectives and potential sources of decisional bias in contexts of uncertainty (proximate solution) and data sharing to enhance clinical knowledge and discovery (ultimate solution).

We would like to acknowledge Dr. Peter Zuk for his contributions to managing and reflecting on the data used for this paper.

The study was reviewed and approved by the Baylor College of Medicine Institutional Review Board (Approval# H-45996), which also waived a requirement for written consent for this project; thus, participants provided verbal consent.

The authors have no conflicts of interest to declare.

Research reported in this publication was supported by the National Institute of Mental Health under Award Number 1RF1MH121371. It was also supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number P50HD103555 for use of the Translational Core Facilities. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

K.K.-Q. wrote the first draft, while K.K.-Q., L.T., K.M., C.S., E.S., J.B.-B., and G.L.-M. commented, added to, and modified subsequent drafts. L.T. and K.M. were involved in data collection and management. L.K. and K.K.-Q. conducted the analysis for this paper. The paper was jointly conceptualized by K.K.-Q., E.S., J.B.-B., and G.L.-M.

Data are not publicly available due to ethical reasons. Further inquiries can be directed to the corresponding author (K.K.-Q.).