Central Thalamic Deep Brain Stimulation Research Articles

Subject and Family Perspectives from the Central Thalamic Deep Brain Stimulation Trial for Traumatic Brain Injury: Part II.

This is the second paper in a two-part series describing subject and family perspectives from the CENTURY-S (CENtral Thalamic Deep Brain Stimulation for the Treatment of Traumatic Brain InjURY-Safety) first-in-human invasive neurological device trial to achieve cognitive restoration in moderate to severe traumatic brain injury (msTBI). To participate, subjects were independently assessed to formally establish decision-making capacity to provide voluntary informed consent. Here, we report on post-operative interviews conducted after a successful trial of thalamic stimulation. All five msTBI subjects met a pre-selected primary endpoint of at least a 10% improvement in completion time on Trail-Making-Test Part B, a marker of executive function. We describe narrative responses of subjects and family members, refracted against that success. Interviews following surgery and the stimulation trial revealed the challenge of adaptation to improvements in cognitive function and emotional regulation as well as altered (and restored) relationships and family dynamics. These improvements exposed barriers to social reintegration made relevant by recoveries once thought inconceivable. The study's success sparked concerns about post-trial access to implanted devices, financing of device maintenance, battery replacement, and on-going care. Most subjects and families identified the need for supportive counseling to adapt to the new trajectory of their lives.

Regulation of arousal and performance of a healthy non-human primate using closed-loop central thalamic deep brain stimulation.

Application of closed-loop approaches in systems neuroscience and brain-computer interfaces holds great promise for revolutionizing our understanding of the brain and for developing novel neuromodulation strategies to restore lost function. The anterior forebrain mesocircuit (AFM) of the mammalian brain is hypothesized to underlie arousal regulation of the cortex and striatum, and support cognitive functions during wakefulness. Dysfunction of arousal regulation is hypothesized to contribute to cognitive dysfunctions in various neurological disorders, and most prominently in patients following traumatic brain injury (TBI). Several clinical studies have explored the use of daily central thalamic deep brain stimulation (CT-DBS) within the AFM to restore consciousness and executive attention in TBI patients. In this study, we explored the use of closed-loop CT-DBS in order to episodically regulate arousal of the AFM of a healthy non-human primate (NHP) with the goal of restoring behavioral performance. We used pupillometry and near real-time analysis of ECoG signals to episodically initiate closed-loop CT-DBS and here we report on our ability to enhance arousal and restore the animal's performance. The initial computer based approach was then experimentally validated using a customized clinical-grade DBS device, the DyNeuMo-X, a bi-directional research platform used for rapidly testing closed-loop DBS. The successful implementation of the DyNeuMo-X in a healthy NHP supports ongoing clinical trials employing the internal DyNeuMo system (NCT05437393, NCT05197816) and our goal of developing and accelerating the deployment of novel neuromodulation approaches to treat cognitive dysfunction in patients with structural brain injuries and other etiologies.

Subject and Family Perspectives from the Central Thalamic Deep Brain Stimulation for Traumatic Brain Injury Study: Part I.

This is the first article in a two-part series describing subject and family perspectives from the central thalamic deep brain stimulation for the treatment of traumatic brain injury using the Medtronic PC+S first-in-human invasive neurological device trial to achieve cognitive restoration in moderate to severe traumatic brain injury, with subjects who were deemed capable of providing voluntary informed consent. In this article, we report on interviews conducted prior to surgery wherein we asked participants about their experiences recovering from brain injury and their perspectives on study enrollment and participation. We asked how risks and benefits were weighed, what their expectations and fears were, and how decisions were reached about trial participation. We found that informed consent and enrollment decisions are fraught. Subjects and families were often split, with subjects more focused on putative benefits and families concerned about incremental risk. Both subjects and families viewed brain injury as disruptive to personal identity and relationships. As decisions were made about study enrollment, families struggled with recognizing the re-emergent agency of subjects and ceding decision-making authority to subjects who had previously been dependent upon them for protection and guidance. Subjects and family members reported a hope for the relief of cognitive disabilities, improved quality of life, normalization of interpersonal interactions, and a return to work or school as reasons for study participation, along with altruism and a desire to advance science. Despite these aspirations, both subjects and families appreciated the risks of the intervention and did not suffer from a therapeutic misconception. A second essay to be published in the next issue of Cambridge Quarterly of Healthcare Ethics-Clinical Neuroethics will describe interviews conducted after surgery, the effects of cognitive restoration for subjects, families, and challenges presented to the social structures they will call upon to support them through recovery. This subsequent article will be available online prior to its formal publication in October 2023.

O017 / #712 SELECTIVE ACTIVATION OF CENTRAL THALAMIC FIBER PATHWAY FACILITATES BEHAVIORAL PERFORMANCE IN HEALTHY NON-HUMAN PRIMATES: TRACK 2: DEEP BRAIN STIMULATION FOR MOVEMENT DISORDERS

The central thalamus (CT) is a key node in the arousal regulation network of the mammalian brain hypothesized to modulate large-scale activity patterns across the anterior forebrain in response to internal and external demands during wakefulness. Damage of the CT in humans, due to traumatic brain injury (TBI) or stroke, results in enduring cognitive deficits in the allocation of attention, maintenance of concentration and focus, working memory, impulse control, processing speed, and motivation. Central thalamic deep brain stimulation (CT-DBS) is an investigational therapy to treat these enduring cognitive dysfunctions, however, the mechanisms of CT-DBS promoting restoration of cognitive function are unknown, and the heterogeneous etiology and recovery profiles in structurally brain injured (SBI) patients contribute to variable outcomes using conventional DBS strategies that may have off-target effects due to activation of multiple pathways.

Clinical and neurophysiological effects of central thalamic deep brain stimulation in the minimally conscious state after severe brain injury

Deep brain stimulation (DBS) of the central thalamus is an experimental treatment for restoration of impaired consciousness in patients with severe acquired brain injury. Previous results of experimental DBS are heterogeneous, but significant improvements in consciousness have been reported. However, the mechanism of action of DBS remains unknown. We used magnetoencephalography to study the direct effects of DBS of the central thalamus on oscillatory activity and functional connectivity throughout the brain in a patient with a prolonged minimally conscious state. Different DBS settings were used to improve consciousness, including two different stimulation frequencies (50 Hz and 130 Hz) with different effective volumes of tissue activation within the central thalamus. While both types of DBS resulted in a direct increase in arousal, we found that DBS with a lower frequency (50 Hz) and larger volume of tissue activation was associated with a stronger increase in functional connectivity and neural variability throughout the brain. Moreover, this form of DBS was associated with improvements in visual pursuit, a reduction in spasticity, and improvement of swallowing, eight years after loss of consciousness. However, after DBS, all neurophysiological markers remained significantly lower than in healthy controls and objective increases in consciousness remained limited. Our findings provide new insights on the mechanistic understanding of neuromodulatory effects of DBS of the central thalamus in humans and suggest that DBS can re-activate dormant functional brain networks, but that the severely injured stimulated brain still lacks the ability to serve cognitive demands.

Dignity of Risk, Reemergent Agency, and the Central Thalamic Stimulation Trial for Moderate to Severe Brain Injury.

This article discusses the utility of Perske's "dignity of risk" as a useful heuristic to explain the consent process for a study to evaluate central thalamic deep brain stimulation as a means to restore cognitive function in moderate to severe brain injury. Narratives of interviews with subjects and their families from a related BRAIN Initiative study reveal discordant views on risk, with subjects being more risk-tolerant than their loved ones. This is a challenge for families who remain protective of subjects who have recovered to the point that they are capable of independent decision-making. While the legal threshold for consent has been met, normative and psychological challenges remain as families accommodate themselves to the reemergent agency of the subject. Dignity of risk is a constructive framework to apprehend how families come to appreciate the primacy of the subject's voice and affirm their reemergent agency following a devastating brain injury.

Sleep Treatments in Disorders of Consciousness: A Systematic Review.

Sleep disorders are among the main comorbidities in patients with a Disorder of Consciousness (DOC). Given the key role of sleep in neural and cognitive functioning, detecting and treating sleep disorders in DOCs might be an effective therapeutic strategy to boost consciousness recovery and levels of awareness. To date, no systematic reviews have been conducted that explore the effect of sleep treatments in DOCs; thus, we systematically reviewed the existing studies on both pharmacological and non-pharmacological treatments for sleep disorders in DOCs. Among 2267 assessed articles, only 7 were included in the systematic review. The studies focused on two sleep disorder categories (sleep-related breathing disorders and circadian rhythm dysregulation) treated with both pharmacological (Modafinil and Intrathecal Baclofen) and non-pharmacological (positive airway pressure, bright light stimulation, and central thalamic deep brain stimulation) interventions. Although the limited number of studies and their heterogeneity do not allow generalized conclusions, all the studies highlighted the effectiveness of treatments on both sleep disorders and levels of awareness. For this reason, clinical and diagnostic evaluations able to detect sleep disorders in DOC patients should be adopted in the clinical routine for the purpose of intervening promptly with the most appropriate treatment.

Selective activation of central thalamic fiber pathway facilitates behavioral performance in healthy non-human primates

Central thalamic deep brain stimulation (CT-DBS) is an investigational therapy to treat enduring cognitive dysfunctions in structurally brain injured (SBI) patients. However, the mechanisms of CT-DBS that promote restoration of cognitive functions are unknown, and the heterogeneous etiology and recovery profiles of SBI patients contribute to variable outcomes when using conventional DBS strategies,which may result in off-target effects due to activation of multiple pathways. To disambiguate the effects of stimulation of two adjacent thalamic pathways, we modeled and experimentally compared conventional and novel ‘field-shaping’ methods of CT-DBS within the central thalamus of healthy non-human primates (NHP) as they performed visuomotor tasks. We show that selective activation of the medial dorsal thalamic tegmental tract (DTTm), but not of the adjacent centromedian-parafascicularis (CM-Pf) pathway, results in robust behavioral facilitation. Our predictive modeling approach in healthy NHPs directly informs ongoing and future clinical investigations of conventional and novel methods of CT-DBS for treating cognitive dysfunctions in SBI patients, for whom no therapy currently exists.

Uncovering the Modulatory Interactions of Brain Networks in Cognition with Central Thalamic Deep Brain Stimulation Using Functional Magnetic Resonance Imaging

Deep brain stimulation (DBS) is a promising treatment for neurological and psychiatric disorders. It acts by altering brain networks and facilitating synaptic plasticity. For enhancing cognitive functions, the central thalamus (CT) has been shown to be a potential DBS target. The network-level mechanisms contributing to the effect exerted by DBS on the CT (CT-DBS) remain unknown. Combining CT-DBS with functional magnetic resonance imaging (fMRI), this study explored brain areas activated while applying CT-DBS in rats, using a newly developed neural probe that was compatible with MRI and could minimize the image distortion and resolve safety issues. Results showed activation of the anterior cingulate cortex, motor cortex, primary and secondary somatosensory cortices, caudate putamen, hypothalamus, thalamus, and hippocampus, suggesting that the corticostriatal, corticolimbic, and thalamocortical brain networks were affected. Behaviorally, the CT-DBS group required a shorter time than sham controls to learn a water-reward lever-pressing task and made more correct choices in a T-maze task. Concurrent with enhanced learning performance, bilateral CT-DBS resulted in alteration in the functional connectivity of brain networks determined by resting-state fMRI. Western blot analyses showed that the protein level of both dopamine D1 and α4-nicotinic acetylcholine receptors was increased, and dopamine D2 receptor was decreased. These data suggest that CT-DBS can enhance cognitive performance as well as brain connectivity through the modulation of synaptic plasticity, such that CT is a target providing high potential for the remediation of acquired cognitive learning and memory disabilities.

Modulation of Theta-Band Local Field Potential Oscillations Across Brain Networks With Central Thalamic Deep Brain Stimulation to Enhance Spatial Working Memory.

Deep brain stimulation (DBS) is a well-established technique for the treatment of movement and psychiatric disorders through the modulation of neural oscillatory activity and synaptic plasticity. The central thalamus (CT) has been indicated as a potential target for stimulation to enhance memory. However, the mechanisms underlying local field potential (LFP) oscillations and memory enhancement by CT-DBS remain unknown. In this study, we used CT-DBS to investigate the mechanisms underlying the changes in oscillatory communication between the CT and hippocampus, both of which are involved in spatial working memory. Local field potentials (LFPs) were recorded from microelectrode array implanted in the CT, dentate gyrus, cornu ammonis (CA) region 1, and CA region 3. Functional connectivity (FC) strength was assessed by LFP–LFP coherence calculations for these brain regions. In addition, a T-maze behavioral task using a rat model was performed to assess the performance of spatial working memory. In DBS group, our results revealed that theta oscillations significantly increased in the CT and hippocampus compared with that in sham controls. As indicated by coherence, the FC between the CT and hippocampus significantly increased in the theta band after CT-DBS. Moreover, Western blotting showed that the protein expressions of the dopamine D1 and α4-nicotinic acetylcholine receptors were enhanced, whereas that of the dopamine D2 receptor decreased in the DBS group. In conclusion, the use of CT-DBS resulted in elevated theta oscillations, increased FC between the CT and hippocampus, and altered synaptic plasticity in the hippocampus, suggesting that CT-DBS is an effective approach for improving spatial working memory.

MR imaging central thalamic deep brain stimulation restored autistic-like social deficits in the rat

BackgroundSocial deficit is a core symptom in autism spectrum disorder (ASD). Although deep brain stimulation (DBS) has been proposed as a potential treatment for ASD, an ideal target nucleus is yet to be identified. DBS at the central thalamic nucleus (CTN) is known to alter corticostriatal and limbic circuits, and subsequently increase the exploratory motor behaviors, cognitive performance, and skill learning in neuropsychiatric and neurodegenerative disorders. ObjectiveWe first investigated the ability of CTN-DBS to selectively engage distinct brain circuits and compared the spatial distribution of evoked network activity and modulation. Second, we investigated whether CTN-DBS intervention improves social interaction in a valproic acid–exposed ASD rat offspring model. MethodsBrain regions activated through CTN-DBS by using a magnetic resonance (MR)-compatible neural probe, which is capable of inducing site-selective microstimulations during functional MRI (fMRI), were investigated. We then performed functional connectivity MRI, the three-chamber social interaction test, and Western blotting analyses to evaluate the therapeutic efficacy of CTN-DBS in an ASD rat offspring model. ResultsThe DBS-evoked fMRI results indicated that the activated brain regions were mainly located in cortical areas, limbic-related areas, and the dorsal striatum. We observed restoration of brain functional connectivity (FC) in corticostriatal and corticolimbic circuits after CTN-DBS, accompanied with increased social interaction and decreased social avoidance in the three-chamber social interaction test. The dopamine D2 receptor decreased significantly after CTN-DBS treatment, suggesting changes in synaptic plasticity and alterations in the brain circuits. ConclusionsApplying CTN-DBS to ASD rat offspring increased FC and altered the synaptic plasticity in the corticolimbic and the corticostriatal circuits. This suggests that CTN-DBS could be an effective treatment for improving the social behaviors of individuals with ASD.

Daytime Central Thalamic Deep Brain Stimulation Modulates Sleep Dynamics in the Severely Injured Brain: Mechanistic Insights and a Novel Framework for Alpha-Delta Sleep Generation.

Loss of organized sleep electrophysiology is a characteristic finding following severe brain injury. The return of structured elements of sleep architecture has been associated with positive prognosis across injury etiologies, suggesting a role for sleep dynamics as biomarkers of wakeful neuronal circuit function. In a continuing study of one minimally conscious state patient studied over the course of ~8½ years, we sought to investigate whether changes in daytime brain activation induced by central thalamic deep brain stimulation (CT-DBS) influenced sleep electrophysiology. In this patient subject, we previously reported significant improvements in sleep electrophysiology during 5½ years of CT-DBS treatment, including increased sleep spindle frequency and SWS delta power. We now present novel findings that many of these improvements in sleep electrophysiology regress following CT-DBS discontinuation; these regressions in sleep features correlate with a significant decrease in behavioral responsiveness. We also observe the re-emergence of alpha-delta sleep, which had been previously suppressed by daytime CT-DBS in this patient subject. Importantly, CT-DBS was only active during the daytime and has been proposed to mediate recovery of consciousness by driving synaptic activity across frontostriatal systems through the enhancement of thalamocortical output. Accordingly, the improvement of sleep dynamics during daytime CT-DBS and their subsequent regression following CT-DBS discontinuation implicates wakeful synaptic activity as a robust modulator of sleep electrophysiology. We interpret these findings in the context of the “synaptic homeostasis hypothesis,” whereby we propose that daytime upregulation of thalamocortical output in the severely injured brain may facilitate organized frontocortical circuit activation and yield net synaptic potentiation during wakefulness, providing a homeostatic drive that reconstitutes sleep dynamics over time. Furthermore, we consider common large-scale network dynamics across several neuropsychiatric disorders in which alpha-delta sleep has been documented, allowing us to formulate a novel mechanistic framework for alpha-delta sleep generation. We conclude that the bi-directional modulation of sleep electrophysiology by daytime thalamocortical activity in the severely injured brain: (1) emphasizes the cyclical carry-over effects of state-dependent circuit activation on large-scale brain dynamics, and (2) further implicates sleep electrophysiology as a sensitive indicator of wakeful brain activation and covert functional recovery in the severely injured brain.

Editorial introductions

Editorial introductions

Robust modulation of arousal regulation, performance, and frontostriatal activity through central thalamic deep brain stimulation in healthy nonhuman primates.

The central thalamus (CT) is a key component of the brain-wide network underlying arousal regulation and sensory-motor integration during wakefulness in the mammalian brain. Dysfunction of the CT, typically a result of severe brain injury (SBI), leads to long-lasting impairments in arousal regulation and subsequent deficits in cognition. Central thalamic deep brain stimulation (CT-DBS) is proposed as a therapy to reestablish and maintain arousal regulation to improve cognition in select SBI patients. However, a mechanistic understanding of CT-DBS and an optimal method of implementing this promising therapy are unknown. Here we demonstrate in two healthy nonhuman primates (NHPs), Macaca mulatta, that location-specific CT-DBS improves performance in visuomotor tasks and is associated with physiological effects consistent with enhancement of endogenous arousal. Specifically, CT-DBS within the lateral wing of the central lateral nucleus and the surrounding medial dorsal thalamic tegmental tract (DTTm) produces a rapid and robust modulation of performance and arousal, as measured by neuronal activity in the frontal cortex and striatum. Notably, the most robust and reliable behavioral and physiological responses resulted when we implemented a novel method of CT-DBS that orients and shapes the electric field within the DTTm using spatially separated DBS leads. Collectively, our results demonstrate that selective activation within the DTTm of the CT robustly regulates endogenous arousal and enhances cognitive performance in the intact NHP; these findings provide insights into the mechanism of CT-DBS and further support the development of CT-DBS as a therapy for reestablishing arousal regulation to support cognition in SBI patients.

Central thalamic deep brain stimulation to support anterior forebrain mesocircuit function in the severely injured brain.

This integrative review frames a general rationale for the use of central thalamic deep brain stimulation (CT-DBS) to support arousal regulation mechanisms in the severely injured brain. The organizing role of the anterior forebrain mesocircuit in recovery mechanisms following widespread deafferentation produced by multi-focal structural brain injuries is emphasized. The mesocircuit model provides the conceptual foundation for the key role of the central thalamus as a privileged node for neuromodulation to support forebrain arousal regulation. In this context, cellular mechanisms arising at the neocortical, striatal, and thalamic population level are considered in the assessment of an individual patient's capacity for harboring underlying reserve that could be recruited for further recovery. Recent preclinical studies and pilot clinical results are compared to frame the detailed rationale for CT-DBS. Application of CT-DBS across the range of outcomes following severe-to-moderate brain injuries is discussed with the aim of improving consciousness and cognition in patients with non-progressive brain injuries.

Central Thalamic Deep-Brain Stimulation Alters Striatal-Thalamic Connectivity in Cognitive Neural Behavior.

Central thalamic deep brain stimulation (CT-DBS) has been proposed as an experimental therapeutic approach to produce consistent sustained regulation of forebrain arousal for several neurological diseases. We investigated local field potentials (LFPs) induced by CT-DBS from the thalamic central lateral nuclei (CL) and the striatum as potential biomarkers for the enhancement of lever-pressing skill learning. LFPs were simultaneously recorded from multiple sites in the CL, ventral striatum (Vstr), and dorsal striatum (Dstr). LFP oscillation power and functional connectivity were assessed and compared between the CT-DBS and sham control groups. The theta and alpha LFP oscillations were significantly increased in the CL and striatum in the CT-DBS group. Furthermore, interhemispheric coherences between bilateral CL and striatum were increased in the theta band. Additionally, enhancement of c-Fos activity, dopamine D2 receptor (Drd2), and α4-nicotinic acetylcholine receptor (α4-nAChR) occurred after CT-DBS treatment in the striatum and hippocampus. CT-DBS strengthened thalamic-striatal functional connectivity, which demonstrates that the inter-regional connectivity enhancement might contribute to synaptic plasticity in the striatum. Altered dopaminergic and cholinergic receptors resulted in modulation of striatal synaptic plasticity's ability to regulate downstream signaling cascades for higher brain functions of lever-pressing skill learning.

Modulation of central thalamic oscillations during emotional-cognitive processing in chronic disorder of consciousness

We report on thalamic recordings in a patient with chronic disorder of consciousness (DOC). Implantation of central thalamic deep brain stimulation (CT-DBS) electrodes was chosen, as this treatment has been reported to display beneficial effects with respect to behavioural responsiveness in DOC. Local field potential (LFP) oscillations were recorded from central thalamic electrodes and their changes elicited by speech stimuli consisting either of familiar voices addressing the patient or unfamiliar non-addressing phrases were studied. In response to familiar-addressing speech we observed modulation of oscillatory activity in the beta and theta band within the central thalamus accompanied by an increase in thalamocortical coherence in the theta band. Furthermore, the theta phase was coupled to the amplitude of gamma locally in the thalamus. These findings indicate a local and long-range cross-frequency response which is not only indicative of the principle involvement of the central thalamus in processing emotional and cognitive information, but also point towards intact physiological functions that may serve as a marker in diagnosing DOC patients and determining novel targets and parameters concerning therapeutic efforts.

Moving toward a generalizable application of central thalamic deep brain stimulation for support of forebrain arousal regulation in the severely injured brain.

This review considers the challenges ahead for developing a generalizable strategy for the use of central thalamic deep brain stimulation (CT/DBS) to support arousal regulation mechanisms in the severely injured brain. Historical efforts to apply CT/DBS to patients with severe brain injuries and a proof-of-concept result from a single-subject study are discussed. Circuit and cellular mechanisms underlying the recovery of consciousness are considered for their relevance to the application of CT/DBS, to improve consciousness and cognition in nonprogressive brain injuries. Finally, directions for development, and testing of generalizable criteria for CT/DBS are suggested, which aim to identify neuronal substrates and behavioral profiles that may optimally benefit from support of arousal regulation mechanisms.

Central thalamic deep brain stimulation for cognitive neuromodulation - a review of proposed mechanisms and investigational studies.

We review the history of efforts to apply central thalamic deep brain stimulation (CT/DBS) to restore consciousness in patients in a coma or vegetative state by changing the arousal state. Early experimental and clinical studies, and the results of a recent single-subject human study that demonstrated both immediate behavioral facilitation and carry-over effects of CT/DBS are reviewed. We consider possible mechanisms underlying CT/DBS effects on cognitively-mediated behaviors in conscious patients in light of the anatomical connectivity and physiological specializations of the central thalamus. Immediate and carry-over effects of CT/DBS are discussed within the context of possible effects on neuronal plasticity and gene expression. We conclude that CT/DBS should be studied as a therapeutic intervention to improve impaired cognitive function in severely brain-injured patients who, in addition to demonstrating clinical evidence of consciousness and goal-directed behavior, retain sufficient preservation of large-scale cerebral networks within the anterior forebrain. Although available data provide evidence for proof-of-concept, very significant challenges for study design and development of CT/DBS for clinical use are identified.

Deep Brain Stimulation, Neuroethics, and the Minimally Conscious State

We briefly review the motivation, ethical framing, and results of a recent single-subject study of central thalamic deep brain stimulation (DBS) in a patient remaining in the chronic minimally conscious state (MCS). In the study, a severely brain-injured human subject showed behavioral improvements in attentive responsiveness, limb control, recovery of oral feeding, and spoken language following central thalamic DBS. 1 These findings are placed into the context of, and contrasted with, prior efforts applying thalamic brain stimulation to patients in the vegetative state (VS). Efforts to develop DBS for recovery of function in the setting of disorders of consciousness must meet several challenges presented by the expected wide variance of underlying brain injuries and need to carefully identify potential goals of therapeutic intervention. Although the study involved only a single subject, the results demonstrate a causal relationship between brain stimulation and cognitive recovery. The generalizability of these findings is completely unknown and the complexity of the problem will require careful and systematic research to move forward.