Pharyngeal Structure and Dysphagia in Patients with Parkinson's Disease and Related Disorders.

Pharyngeal muscle changes occur in patients with Parkinson's disease and related disorders (PRD); however, the association between the structural alterations in the pharynx and the symptoms of dysphagia remains unclear. We assessed structural changes and contractile forces by measuring pharyngeal wall thickness and width. We aimed to define the pharyngeal measurements and determine their value as diagnostic tools for dysphagia. The pharyngeal wall thickness (PWT), pharyngeal width at rest (PWR), and shortest pharyngeal width at swallowing (PWS) were measured using lateral neck roentgenograms and videofluoroscopic swallowing study. We compared the PWR and PWT between the PRD and control groups using an independent t-test. The Kendall correlation test was performed on the radiological data of the pharynx (PWT, PWR and PWS), dysphagia scales (Penetration-Aspiration scale [PAS] and Dysphagia Outcome and Severity Scale [DOSS]), and Hoehn and Yahr scale (HY scale). The PWT was smaller and the PWR greater in the PRD than in the control group (p < 0.05). The dysphagia scales (PAS and DOSS) were correlated with the radiological data (PWT and PWS) and the HY scale (p < 0.05). The HY scale score also correlated with the PWT (p < 0.05). The optimal cutoff points of the PWT and PWR for predicting aspiration were 4.05 and 16.05 mm in the PRD group, respectively. Using the PWT, PWR and PWS, muscle atrophy and contractile strength of the pharynx can be estimated. The combination of the PWT and PWR can be a simple indicator for predicting swallowing disorders at the bedside.

Factors Affecting Participation in Telerehabilitation Using Transcranial Direct Current Stimulation for Patients with Poststroke Paralysis in South Korea.

Background: The coronavirus disease 2019 pandemic has expanded noncontact health care systems worldwide. Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technology that enables treatment monitoring under remote supervision. We investigated the factors affecting patients' decision to participate in telerehabilitation (TR) using tDCS for motor function recovery after suffering a stroke. Materials and Methods: Four medical institutions surveyed 156 patients with poststroke paralysis. The participants were asked whether they would participate in TR therapy using tDCS in the future. We performed logistic regression analysis to examine the factors-demographic data, stroke characteristics, arm function, gait, and cognitive function-that influenced participants' decisions. Results: Of the participants, 66% (103/156) reported that they would participate in TR using tDCS in the future. Participants' monthly salary was a single significant independent factor influencing their decision to participate. Those earning greater than 5 million KRW (4,000 USD) were more likely to engage in TR via tDCS than those earning less than 1 million KRW (800 USD). The most common barriers to participation in telemedicine included the preference for face-to-face treatment and unfamiliarity. The expected medical expenses of TR using tDCS were 46,154 KRW (37 USD) per session. Conclusions: Most participants with poststroke paralysis responded positively to TR using tDCS for hand function recovery. For telemedicine to work effectively in a situation wherein face-to-face rehabilitation is impossible, prior discussion at the governmental level is essential for determining medical finances.

Effects of transcranial direct current stimulation on cortex modulation by stimulation of the primary motor cortex and parietal cortex in humans.

AIM OF THE STUDY: Transcranial magnetic stimulation (TMS) is used to measure corticospinal excitability (CSE) from the primary motor cortex (M1) in humans through motor-evoked potentials (MEPs). The variability of CSE responses to transcranial direct current stimulation (tDCS) protocols is high and needs to be reproduced in the healthy population. The M1 and posterior parietal cortex (PPC) are anatomically and functionally connected and could play a role in understanding the variability in CSE responses. We tested the individual MEPs following a common cathodal (ctDCS) protocol over the M1 and PPC. MATERIALS AND METHODS: Twenty-eight healthy subjects were randomized for a ctDCS stimulation over the left M1 and PPC for 20 min on a separate days. The first dorsal interosseous muscle (FDI) contralateral stimulation of the left M1 was used as the resting motor threshold (RMT), while 15 single pulses 4-8 s apart at an intensity of 120% RMT were used to determine the baseline MEP amplitude and at T0, 5, 10, 20, 30, 40, 50, and 60 min after ctDCS stimulation in both sessions. RESULTS: A 20 min duration of ctDCS stimulation significantly deceased the CSE only at T0 (p = 0.046 at M1, p = 0.010 at PPC). CONCLUSION: Our results suggested that PPC stimulation can modulate M1 excitability and PPC-M1 connectivity, but a significant effect is only observed immediately post ctDCS. The tDCS showed variability in response to the tDCS protocol is consistent with other non-invasive brain stimulation studies.

The functional relevance of diffusion tensor imaging in comparison to conventional MRI in patients with cervical compressive myelopathy.

OBJECTIVE: To determine the functional relevance of diffusion tensor imaging (DTI) metrics and conventional MRI (signal intensity change in T2, compression ratio) by measuring the correlation of these parameters with clinical outcome measured by the modified Japanese Orthopedic Association (mJOA) score. MATERIALS AND METHODS: A total of 20 cervical myelopathy (CM) patients participated in this prospective cohort study. The severities of CM were assessed using the mJOA score. Conventional MRIs (T2-weighted images) measuring the signal changes of spinal cords and the degree of compression at the lesion level and DTI metrics [fractional anisotropy (FA), apparent diffusion coefficient (ADC)] at each lesion and below each lesion (C7/T1) level were acquired using a 3-T Achieva MRI. These parameters were correlated with the mJOA scores to determine the functional relevance. RESULTS: Ninety percent of CM patients showed signal changes and 30 % of patients noted a more than 40% canal compression ratio in conventional MRIs at the lesion level; however, these findings were not correlated with the mJOA score (p < 0.05). In contrast, FA values on DTI showed high sensitivity to CM (100%), which was well correlated with the mJOA score (p = 0.034, r = 0.475) below the lesion level (C7/T1). CONCLUSIONS: This study showed a meaningful symptomatic correlation between mJOA scores and FA values below the lesion levels in CM patients. It could give us more understanding of the pathological changes in spinal cords matched with various clinical findings in CM patients than the results from conventional MRI.

Pedicle screw fixation and posterior fusion for lumbar degenerative diseases: effects on individual paraspinal muscles and lower back pain; a single-center, prospective study.

BACKGROUND: To the best of our knowledge, there have been no reports on the points at which the denervated multifidus and erector spinae muscles become reinnervated after pedicle screw fixation and posterior fusion in patients with lumbar degenerative diseases. Our study was designed to confirm reinnervation of denervated paraspinal muscles following pedicle screw fixation and posterior fusion and to confirm alleviation of the patients' lower back pain (LBP). METHODS: In this prospective study, we enrolled 67 patients who had undergone pedicle screw fixation and posterior fusion. The surgery had alleviated their leg pain, but the patients complained of LBP at the L3-5 level 3 months after the surgery. The patients were divided into two groups (I and II) according to the level at which pain was experienced. Paraspinal mapping scores were recorded preoperatively and 3, 6, 12, and 18 months postoperatively. Oswestry Disability Index and visual analogue scale scores were determined. Regression analyses using a general linear model and a mixed model were performed. RESULTS: Pedicle screw fixation and posterior fusion significantly denervated the multifidus and erector spinae not only in the surgical segment, but also in adjacent segments. Group I patients displayed reinnervation in the denervated erector spinae and multifidus muscles at 12 and 18 months, respectively. In contrast, group II showed reinnervation only in of the denervated erector spinae of the upper segment at 18 months, with no other areas of reinnervation. Postoperative LBP was significantly diminished at 12 months in group I and at 18 months in group II. There was also significantly less LBP at 6 months (prior to reinnervation of the paraspinal muscles). CONCLUSIONS: The denervated multifidus and erector spinae muscles at L4-5, which had been denervated using pedicle screw fixation and posterior fusion, were significantly reinnervated at 18 months postoperatively, whereas patients with denervation at L3-5 had only a tendency to be reinnervated at follow-up. Postoperative LBP in these patients was significantly diminished at the follow-up visits.

Cognitive Dysfunction in Drug-induced Parkinsonism Caused by Prokinetics and Antiemetics.

The use of prokinetics/antiemetics is one of the leading causes of drug-induced parkinsonism (DIP) observed in neurology clinics. Cognitive dysfunction in DIP has recently been recognized, but pathologies related with cognitive dysfunction is unknown. Among our retrospective cohort of 385 consecutive parkinsonian patients enrolled in our parkinsonism registry, 14 patients were identified who satisfied our inclusion criteria: parkinsonism caused by prokinetics/antiemetics, existing T1-weighted 3D volumetric MR images, and normal [(18)F]-N-3-fluoropropyl-2-ß-carboxymethoxy-3-ß-(4-iodophenyl) nortropane PET scan images. For the comparison of volumetric MR data, 30 age- and sex-matched healthy individuals were included in this study. Among 14 patients with DIP, 4 patients were diagnosed with dementia, and all other patients had mild cognitive impairment (MCI). Comparisons of MR volumetric data between DIP patients with MCI and controls show that cortical gray matter volumes are reduced bilaterally in DIP (P=0.041) without changes in either total white matter volume or total intracranial volume. Among subcortical structures, the volume of the right hippocampus is reduced in DIP patients compared with controls (P=0.011, uncorrected). In DIP, cortical thickness is reduced in the bilateral lingual (P=0.002), right fusiform (P=0.032) and part of the left lateral occipital gyri (P=0.007). Our results suggests that cognitive dysfunction in DIP caused by prokinetics/antiemetics is common. Structural changes in the brain by 3D MRI may be associated with cognitive decline in DIP.

Effects of anodal transcranial direct current stimulation on postural stability in subacute stroke: A randomized control trial.

Anodal transcranial direct current stimulation (tDCS) promotes neuromodulation and neuroplasticity in the brain. The aim of this study was to determine the long-term effects of the anodal tDCS on postural and trunk stability, physical performance, anticipatory postural adjustment and quality of life in sub-acute stroke patients. Thirty-six participants with sub-acute stroke were divided into experimental and control groups using sealed envelope randomization. Outcome measures comprised the Postural Assessment Scale for Stroke, Trunk Impairment Scale, Time Up and Go Test, Functional Reach Test, and Stroke-Specific Quality of Life Scale. Assessments were conducted at 0, 3, 6, 9, and 12 weeks. Within-group analysis revealed significant improvement in both the experimental (p-value < 0.05) and control groups (p-value < 0.005). Notably, significant effects were observed in postural stability after intervention, and during one of the detraining assessments, the experimental group showed superior results compared to the control group in subacute stroke. Anodal tDCS yield significant short- and long-term effects on postural stability, while short term effects on trunk stability. Additionally, long term effects were observed on the physical performance and anticipatory postural adjustments while no effects at quality of life either short or long term basis among the subacute stroke patients.

Insights on the neural basis of motor plasticity induced by theta burst stimulation from TMS-EEG.

Transcranial magnetic stimulation (TMS) is a useful tool to induce and measure plasticity in the human brain. However, the cortical effects are generally indirectly evaluated with motor-evoked potentials (MEPs) reflective of modulation of cortico-spinal excitability. In this study, we aim to provide direct measures of cortical plasticity by combining TMS with electroencephalography (EEG). Continuous theta-burst stimulation (cTBS) was applied over the primary motor cortex (M1) of young healthy adults, and we measured modulation of (i) MEPs, (ii) TMS-induced EEG evoked potentials (TEPs), (iii) TMS-induced EEG synchronization and (iv) eyes-closed resting EEG. Our results show the expected cTBS-induced decrease in MEP size, which we found to be paralleled by a modulation of a combination of TEPs. Furthermore, we found that cTBS increased the power in the theta band of eyes-closed resting EEG, whereas it decreased single-pulse TMS-induced power in the theta and alpha bands. In addition, cTBS decreased the power in the beta band of eyes-closed resting EEG, whereas it increased single-pulse TMS-induced power in the beta band. We suggest that cTBS acts by modulating the phase alignment between already active oscillators; it synchronizes low-frequency (theta and/or alpha) oscillators and desynchronizes high-frequency (beta) oscillators. These results provide novel insight into the cortical effects of cTBS and could be useful for exploring cTBS-induced plasticity outside of the motor cortex.

Neural plasticity and hemispatial neglect in stroke.

The ability to outline the world and our place in it characterises our humanity. Stroke or brain injury can alter this world-making capability temporarily or permanently. The stroke patient's world, once intelligible and practicable, is transformed into a confusing, unapproachable and hostile environment. The skills of intellect, sensation, awareness and movement, which are honed over the course of a lifetime and which so characterise our humanity are the very abilities most compromised by stroke. Stroke can rob people of the most basic way of interacting with the world. We will outline what is neglect and its mechanism in brain plasticity.

Compensatory Hyperactivity of the Ipsilesional Red Nucleus in a Patient With Somatosensory Cortex Damage: A Case Report.

This case study describes a patient who experienced motor recovery and involuntary movements following damage to the right primary somatosensory cortex caused by an intracranial hemorrhage. The patient initially suffered from paralysis in her left arm and leg, but exhibited significant motor recovery later, accompanied by multiple episodes of ballistic movement during the recovery process. A diffusion tensor imaging analysis was performed to investigate changes in sensorimotor-related brain areas in the patient. The patient had higher fractional anisotropy and lower mean diffusivity values in the ipsilesional red nucleus (RN) than age-matched controls. We assume that hyperactivity of the ipsilesional RN might play a role in motor recovery after damage to the primary somatosensory cortex, potentially through its involvement in sensorimotor integration. Our findings demonstrated the potential for adaptive changes in the ipsilesional RN following damage to the primary somatosensory cortex.

Heterogeneous Diffusion Metrics Patterns in Delayed Encephalopathy After Acute Carbon Monoxide Poisoning: A Case Report.

Delayed encephalopathy (DE) following acute carbon monoxide (CO) poisoning is characterized by a wide range of neurological symptoms, including akinetic mutism, cognitive impairment, and gait disturbances. Herein, we reported the case of a 61-year-old patient with DE after acute CO poisoning, who displayed heterogeneous patterns of cortical and subcortical structural integrity on diffusion tensor imaging (DTI). Four distinct patterns of diffusion tensor metrics (fractional anisotropy [FA] and mean diffusivity [MD]) were observed in the patient compared to age-matched controls (a decrease in FA and an increase in MD, a decrease in FA only, an increase in MD only, and an increase in FA and MD). This study revealed heterogeneous patterns of cortical and subcortical damage associated with DE after CO poisoning, contributing to a deeper understanding of the diverse clinical symptoms observed in this patient.

Neurobiology of Amphetamine use in Stroke Recovery Combined with Rehabilitative Training and Brain Stimulation.

Stroke is a physiological disorder involving a prolonged local interruption of cerebral blood flow. It leads to massive neuronal death and causes short-term or long-lasting functional impairment. Most stroke victims regain some neural function weeks or months following a stroke, but this recovery can plateau six months or more after the injury. The goal of stroke therapy is the rehabilitation of functional capabilities, especially those affecting the patient's autonomy and quality of life. Recent clinical and animal studies combining acute dextro-amphetamine (d-AMPH) administration with rehabilitative training (RT) have revealed that this treatment has significant remedial effects. The review aims to examine the synergistic therapeutic effects of d-amphetamine coupled with RT, administered during the early or late subacute period, on neuronal activation, anatomic plasticity, and skilled motor function in a middle-aged rodent stroke model. The treatment will also include magnetic field stimulation. This review will help increase understanding of the mechanism of d-amphetamine coupled with RT and magnetic field stimulation and their converging therapeutic effects for stroke recovery.

Role of Thioredoxin System in Regulating Cellular Redox Status in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia and a public health problem. It exhibits significant oxidative stress and redox alterations. The antioxidant enzyme systems defend the cellular environment from oxidative stress. One of the redox systems is the thioredoxin system (TS), which exerts decisive control over the cellular redox environment. We aimed to review the protective effects of TS, which include thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH. In the following, we discussed the physiological functioning and the role of the TS in maintaining the cellular redox-homeostasis in the AD-damaged brain. Trx protects the cellular environment from oxidative stress, while TrxR is crucial for the cellular detoxification of reactive oxygen species in the brain. However, TS dysregulation increases the susceptibility to cellular death. The changes in Trx and TrxR levels are significantly associated with AD progression. Though the data from human, animal, and cellular models support the neuroprotective role of TS in the brain of AD patients, the translational potential of these findings to clinical settings is not yet applied. This review summarizes the current knowledge on the emerging role of the TrxR-Trx system in AD.

Utility of Diffusion and Magnetization Transfer MRI in Cervical Spondylotic Myelopathy: A Pilot Study.

Diffusion tensor imaging (DTI) and magnetization transfer (MT) magnetic resonance imaging (MRI) can help detect spinal cord pathology, and tract-specific analysis of their parameters, such as fractional anisotropy (FA), mean diffusivity, axial diffusivity (AD), radial diffusivity (RD) and MT ratio (MTR), can give microstructural information. We performed the tract-based acquisition of MR parameters of three major motor tracts: the lateral corticospinal (CS), rubrospinal (RuS) tract, and lateral reticulospinal (RS) tract as well as two major sensory tracts, i.e., the fasciculus cuneatus (FC) and spinal lemniscus, to detect pathologic change and find correlations with clinical items. MR parameters were extracted for each tract at three levels: the most compressed lesion level and above and below the lesion. We compared the MR parameters of eight cervical spondylotic myelopathy patients and 12 normal controls and analyzed the correlation between clinical evaluation items and MR parameters in patients. RuS and lateral RS showed worse DTI parameters at the lesion level in patients compared to the controls. Worse DTI parameters in those tracts were correlated with weaker power grasp at the lesion level. FC and lateral CS showed a correlation between higher RD and lower FA and MTR with a weaker lateral pinch below the lesion level.

Transcranial magnetic stimulation in animal models of neurodegeneration.

Brain stimulation techniques offer powerful means of modulating the physiology of specific neural structures. In recent years, non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, have emerged as therapeutic tools for neurology and neuroscience. However, the possible repercussions of these techniques remain unclear, and there are few reports on the incisive recovery mechanisms through brain stimulation. Although several studies have recommended the use of non-invasive brain stimulation in clinical neuroscience, with a special emphasis on TMS, the suggested mechanisms of action have not been confirmed directly at the neural level. Insights into the neural mechanisms of non-invasive brain stimulation would unveil the strategies necessary to enhance the safety and efficacy of this progressive approach. Therefore, animal studies investigating the mechanisms of TMS-induced recovery at the neural level are crucial for the elaboration of non-invasive brain stimulation. Translational research done using animal models has several advantages and is able to investigate knowledge gaps by directly targeting neuronal levels. In this review, we have discussed the role of TMS in different animal models, the impact of animal studies on various disease states, and the findings regarding brain function of animal models after TMS in pharmacology research.

Continuous theta-burst stimulation over the left posterior inferior frontal gyrus induced compensatory plasticity in the language network.

Introduction: Continuous theta-burst stimulation (cTBS) has been used as an effective tool in inducing inhibitory aftereffect within a short time periods in the motor cortex; this has been demonstrated in the language network to a limited degree with controversial effect. In this study, we aimed to delineate the offline effect of cTBS-induced changes to the left posterior inferior frontal gyrus (pIFG) in healthy subjects using functional magnetic resonance imaging (fMRI). Methods: Twenty healthy, normal subjects (mean age: 30.84 years) were recruited. They all were right-handed and had no contra-indications for fMRI or cTBS. They were randomly assigned into the treatment group or the sham control group. Results: ANOVA showed that cTBS had a significant main effect only when the sham treatment was subtracted from the real stimulation in left superior temporal, left inferior frontal gyrus, thalamus, and right insular cortex (uncorrected p < 0.002). The subjects' post-cTBS condition differed significantly from their pre-cTBS condition in the left pIFG (uncorrected p < 0.002). There were interactions in the pIFG, bilateral superior parietal lobules, left superior temporal, left supramarginal, and left cuneus areas. The application of cTBS induced increased BOLD signals in language-related networks by stimulating the left pIFG (BA 44). This implies that inhibiting the pIFG led to increased use of language network resources. Conclusion: This study demonstrated cTBS-induced changes in the language network caused by stimulation of the left pIFG. Based on these findings, future studies on the therapeutic effects of cTBS on the right Broca's homolog area are warranted.

Relationship between lower limb muscle activity and cortical activation among elderly people during walking: Effects of fast speed and cognitive dual task.

Objective: Gait is a complex behavior that involves not only the musculoskeletal system, but also higher-order brain functions, including cognition. This study was performed to investigate the correlation between lower limb muscle activity and cortical activation during treadmill walking in two groups of elderly people: the young-old (aged 65-74 years) and the old-old (aged 75-84 years). Methods: Thirty-one young-old and 31 old-old people participated in this study. All participants were sequentially subjected to three gait conditions on a treadmill: (1) comfortable walking, (2) fast walking, and (3) cognitive dual-task walking. During treadmill walking, the activity of the lower limb muscles was measured using a surface electromyography system, and cortical activation was measured using a functional near-infrared spectroscopy system. The correlation between muscle activity and cortical activation during treadmill walking was analyzed and compared between the two groups. Results: During comfortable walking, lower extremity muscle activity had a strong correlation with cortical activation, especially in the swing phase; this was significantly stronger in the young-old than the old-old. During fast walking, the correlations between lower limb muscle activity and cortical activation were stronger than those during comfortable walking in both groups. In cognitive dual-task walking, cortical activation in the frontal region and motor area was increased, although the correlation between muscle activity and cortical activation was weaker than that during comfortable walking in both groups. Conclusion: The corticomotor correlation differed significantly between the old-old and the young-old. These results suggest that gait function is compensated by regulating corticomotor correlation as well as brain activity during walking in the elderly. These results could serve as a basis for developing gait training and fall prevention programs for the elderly.

Correlations between COMT polymorphism and brain structure and cognition in elderly subjects: An observational study.

ABSTRACT: The catechol-O-methyltransferase (COMT) gene has been noted to play an important role in individual variations in the aging process. We investigated whether COMT polymorphism could influence cognition related to white matter networks. More specifically, we examined whether methionine (Met) allele loading is associated with better individual cognitive performance. Thirty-four healthy elderly participants were recruited; each participant's COMT genotype was determined, and Korean version of Montreal Cognitive Assessment scores and a diffusion tensor image were obtained for all participants. The Met carrier group showed significantly lower mean diffusivity, axial diffusivity, and radial diffusivity values for the right hippocampus, thalamus, uncinate fasciculus, and left caudate nucleus than the valine homozygote group. The Met carrier group also scored higher for executive function and attention on the Korean version of Montreal Cognitive Assessment. Based on these results, we can assume that the COMT Met allele has a protective effect on cognitive decline contributing to individual differences in cognitive function in late life period.

Effects of transcranial magnetic stimulation on neurobiological changes in Alzheimer's disease (Review).

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline and brain neuronal loss. A pioneering field of research in AD is brain stimulation via electromagnetic fields (EMFs), which may produce clinical benefits. Noninvasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS), have been developed to treat neurological and psychiatric disorders. The purpose of the present review is to identify neurobiological changes, including inflammatory, neurodegenerative, apoptotic, neuroprotective and genetic changes, which are associated with repetitive TMS (rTMS) treatment in patients with AD. Furthermore, it aims to evaluate the effect of TMS treatment in patients with AD and to identify the associated mechanisms. The present review highlights the changes in inflammatory and apoptotic mechanisms, mitochondrial enzymatic activities, and modulation of gene expression (microRNA expression profiles) associated with rTMS or sham procedures. At the molecular level, it has been suggested that EMFs generated by TMS may affect the cell redox status and amyloidogenic processes. TMS may also modulate gene expression by acting on both transcriptional and post­transcriptional regulatory mechanisms. TMS may increase brain cortical excitability, induce specific potentiation phenomena, and promote synaptic plasticity and recovery of impaired functions; thus, it may re­establish cognitive performance in patients with AD.

An Exploration of the Neural Network of Lance-Adams Syndrome: a Case Report.

Lance-Adams syndrome (LAS) is a rare neurological disorder that may occur after cardiopulmonary resuscitation. The LAS is usually caused by hypoxic changes. Neuroimaging studies show that the brain pathology of LAS patients is not uniform, and the pathophysiology of the myoclonus can vary from patient to patient. Our case study contributes to this etiological heterogeneity by neuroimaging and transcranial magnetic stimulation (TMS). In patients with rare brain conditions such as LAS, a combination of brain stimulation methods, such as TMS, and diffusion tensor imaging can provide insights into this condition's pathophysiology. These insights can facilitate the development of more effective therapies.