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References | PMC10439640 | |||
Background: | Parkinson’s disease, PD | These authors contributed equally to this work.Axial symptoms of Parkinson’s disease (PD) can be debilitating and are often refractory to conventional therapies such as dopamine replacement therapy and deep brain stimulation (DBS) of the subthalamic nuclei (STN). | PMC10357146 | |
Objective: | Evaluate the efficacy of bilateral DBS of the pedunculopontine nucleus area (PPNa) and investigate structural and physiological correlates of clinical response. | PMC10357146 | ||
Methods: | A randomized, double-blind, cross-over clinical trial was employed to evaluate the efficacy of bilateral PPNa-DBS on axial symptoms. Lead positions and neuronal activity were evaluated with respect to clinical response. Connectomic cortical activation profiles were generated based on the volumes of tissue activated. | PMC10357146 | ||
Results: | PPNa-DBS modestly improved ( | PMC10357146 | ||
Conclusion: | PD | Bilateral PPNa-DBS influenced gait symptoms in patients with PD. Anatomical and physiological information may aid in localization of a favorable stimulation target. | PMC10357146 | |
INTRODUCTION | Parkinson’s disease, gait disturbances, PD, axial motor symptoms | DISEASE PROGRESSION | Parkinson’s disease (PD) is generally well-managed by dopamine replacement therapy and/or deep brain stimulation (DBS) of the subthalamic nucleus (STN); however, axial motor symptoms can emerge with disease progression, including postural instability and gait disturbances. These features can result in falls and diminis... | PMC10357146 |
METHODS AND MATERIALS | PMC10357146 | |||
Patients | Seven patients were treated with bilateral PPNa-DBS within a controlled clinical trial. Patient information is available in Patient information | PMC10357146 | ||
Surgical procedures | Bilateral electrode implantations (3389 Model, Medtronic, MN, USA) were performed under local anesthesia after overnight withdrawal from anti-parkinsonian medication. The PPNa was targeted via direct localization using a proton-density MRI protocol at 1.5T [ | PMC10357146 | ||
Therapy and stimulation parameters | The optimal stimulation parameters ( | PMC10357146 | ||
Complications and side effects | ischemia, bleeding, transient motor aphasia | ISCHEMIA, BLEEDING, POSTOPERATIVE COMPLICATIONS | MRI images acquired postoperatively showed no abnormalities related to asymptomatic bleeding or ischemia. The following postoperative complications were documented: transient motor aphasia without a morphological MRI correlate and without indications for seizure-typical activity in EEG ( | PMC10357146 |
Study design | micro-lesions | A prospective, randomized, double-blind, cross-over study design was applied with two 2-month treatment periods subsequent to a 2-month postoperative period (see Randomized double-blind cross-over study design. The patients were brought in for baseline evaluations preoperatively. The operation was followed by a two-mon... | PMC10357146 | |
Outcome measures | Parkinson’s Disease Questionnaire (PDQ-39). | SECONDARY, COMPLICATIONS, MOS | Per the registered study protocol, the primary outcome was the “Axial-Score” (UPDRS items 13–15; falling unrelated to freezing, freezing when walking, walking; and 27–31; arising from chair, posture, gait, postural stability, body bradykinesia) comparison between Stim-ON and Stim-OFF, in the medication-OFF condition. A... | PMC10357146 |
Structural and functional connectomic profiles | In additional to structural imaging analyses in stereotactic space, DBS lead localizations were performed in Lead-DBS, as previously described in detail [ | PMC10357146 | ||
RESULTS | PMC10357146 | |||
Trial outcomes | SECONDARY | Complete results including primary and secondary outcome measures and additional findings are available in | PMC10357146 | |
Lead placements | Based on MRI analyses in stereotactic space, more anterior lead placements appeared to be favorable (A) Lead placement correlates, and B) single-unit recordings. A) MRI results suggest that more anterior lead placements were favorable. B) Single-unit recordings show two clusters of neurons (cluster-1 being faster and m... | PMC10357146 | ||
Microelectrode recordings | A correlation fit with a power function ( | PMC10357146 | ||
Structural and functional connectomic profiles | PPNa-DBS leads were localized in Lead-DBS (Lead locations and groupwise structural and functional connectomic profiles. A, B) Reconstructions of all electrodes, C, D) fibers traversing the groupwise VTA, and E) structural and F) functional connectivity profiles. | PMC10357146 | ||
DISCUSSION | Bilateral PPNa-DBS modestly influenced axial features (particularly gait) in the medication-OFF condition. Only two other randomized clinical studies evaluated the efficacy of bilateral PPN-DBS without concurrent STN-DBS [The results of an open-label study (Other double-blind studies which applied different stimulation... | PMC10357146 | ||
Lead placements | The finding that more anterior electrode placements were favorable seemed contradictory to that of Goetz and colleagues [ | PMC10357146 | ||
Single-neuron activity | Assessment of neuronal activity along surgical trajectories suggested that it may be more favorable to target a slower (22.5±6.37 Hz), less regular neuronal population. This observation is in line with a recent report on two cases where similar discharge rates have been detected (19.1±15.1 Hz) [ | PMC10357146 | ||
Structural and functional connectomic profiles | multiple basal ganglia and limbic areas | CORTEX | The PPN has connections with the cerebral cortex, multiple basal ganglia and limbic areas, the thalamus, other brainstem regions, the spinal cord, and the cerebellum. These connections implicate the PPN in a variety of functions including movement, cognition, and sleep. With respect to cortical connectivity, dense proj... | PMC10357146 |
Limitations | PD | The medication-OFF Axial-Score and Gait-Score improvements of 7.7% and 16.3%, respectively, were modest; thus, the results should be interpreted with caution. However, a recent study demonstrated that axial symptom score worsening (the only predictor of mortality in patients with PD) was 27% over the course of 10 years... | PMC10357146 | |
Conclusions | Bilateral PPNa-DBS modestly influenced axial symptoms, particularly with respect to gait, in the medication-OFF condition. Electrode placements near the 50% mark of the PMJ line, where slow irregular neurons were encountered along surgical trajectories, yielded better therapeutic responses. | PMC10357146 | ||
Supplementary Material | PMC10357146 | |||
Supplementary Material | Click here for additional data file. | PMC10357146 | ||
ACKNOWLEDGMENTS | The authors thank the patients for participating in this study and Dr. Ramin Azodi-Avval for his contribution to an earlier version of | PMC10357146 | ||
SUPPLEMENTARY MATERIAL | The supplementary material is available in the electronic version of this article: | PMC10357146 | ||
CONFLICT OF INTEREST | D.W. | FOX | S.B. has ownership interest in Neurostar GmbH (not related to this work). A.G. was supported by research grants (not related to this work) from Medtronic, Boston Scientific, Abbott, the Baden-Wuerttemberg Foundation, and the German Federal Ministry of Education and Research. D.W. has received research support from the ... | PMC10357146 |
DATA AVAILABILITY | The data will be available upon request, as the ethics approval does not allow uploading the datasets to a publicly available repository. | PMC10357146 | ||
REFERENCES | PMC10357146 | |||
Background: | Alzheimer’s disease, AD, cognitive impairment | DISEASE PROGRESSION, DISEASE | Alzheimer’s disease (AD) is a chronic condition marked by progressive objective cognitive impairment (OCI). No monotherapy has substantially altered disease progression, suggesting the disease is multifactorial and may require a multimodal therapeutic approach. | PMC10473097 |
Objective: | infection, cognitive decline | INFECTION | We sought to determine if cognitive function in a sample with OCI would change in response to a multimodal, individualized care plan based on potential contributors to cognitive decline (e.g., nutritional status, infection, etc.). | PMC10473097 |
Methods: | Participants ( | PMC10473097 | ||
Results: | At 6 months, mean MoCA scores improved from 19.6±3.1 to 21.7±6.2 ( | PMC10473097 | ||
Conclusion: | Multiple measures of cognitive function improved after six months of intervention. Our results support the feasibility and impact of a multimodal, individualized treatment approach to OCI, warranting further research. | PMC10473097 | ||
INTRODUCTION | cognitive impairment, MCI, Alzheimer’s disease, debilitating disorder, cognitive decline, AD | Alzheimer’s disease (AD) is a debilitating disorder that affects approximately 6 million people in the United States and 50 million people worldwide [Mild cognitive impairment (MCI), a formal diagnosis that includes measures of both objective cognitive impairment (OCI) and subjective cognitive decline, is a known predi... | PMC10473097 | |
METHODS | PMC10473097 | |||
Design | infection, cognitive decline, traumatic brain injury | INFECTION, RECRUITMENT, SLEEP APNEA | A protocol-driven, uncontrolled, pragmatic trial was used in order to test feasibility and estimate effects in a real-world clinical setting. This research was approved by the Institutional Review Board (IRB) at the National University of Natural Medicine and was registered on ClinicalTrials.gov as NCT04284449. Partici... | PMC10473097 |
Participants and inclusion/exclusion criteria | deafness, cognitive impairment, neurological impairment, MCI, visual impairment, somatic disease, dementia, word of mouth, cognitive decline, substance abuse, congenital cognitive impairment or disability | RECRUITMENT | Recruitment was conducted regionally via flyers, social media, email, physician referral, and word of mouth. Inclusion criteria included the following: age≥45 years; cognitive impairment, as demonstrated by a Montreal Cognitive Assessment (MoCA) of 12–23; ability to independently make decisions or have a legal Health C... | PMC10473097 |
Clinical visit content | A 90-min clinical initial intake visit was conducted for each participant, with subsequent visits lasting from 45–75 min. Clinical visits were usually conducted on the same day as study visits, though participants had the flexibility to schedule clinical visits on days separate from study visits. The baseline clinical ... | PMC10473097 | ||
Laboratory evaluation | blood sugar dysregulation | CHRONIC INFECTION, INFLAMMATION, CARDIOVASCULAR DISEASE | To support diagnosis and the development of an individual treatment plan, extensive analysis of blood, urine, hair, and stool samples were performed through commercial clinical laboratory services. These included biomarkers of environmental toxicant exposure, blood sugar dysregulation, gastrointestinal health, nutrient... | PMC10473097 |
Intervention | PMC10473097 | |||
Individualized treatment | cognitive decline | The intervention consisted of a multimodal, individualized medicine treatment plan (i.e., an approach characteristic of the integrative medical care model), as would happen in a real-world setting. Participants were treated for six months with a treatment plan based on individualized evaluations for the presence or abs... | PMC10473097 | |
Lifestyle treatments | Participants were encouraged to increase exercise and adopt novel exercise routines with the goal of getting regular aerobic and strength training exercise. Exercise recommendations were given after assessment of risk, accessibility, and possible maximal impact to the participant. Depending on participant activity leve... | PMC10473097 | ||
Dietary treatments | To optimize metabolism, a ketogenic diet was encouraged for all participants [All participants received a commercially available nootropic blend including herbs and nutrients, omega-3 s, and vitamin D (see | PMC10473097 | ||
Environmental exposures treatments | low mercury seafood | Strategies to mitigate environmental exposures included: avoidance (e.g., low mercury seafood, mold avoidance or remediation, changes in cleaning or personal care products), support for hepatic detoxification (e.g., herbs, supplemental nutrients, glutathione), binding agents (e.g., cholestyramine, chlorella, charcoal, ... | PMC10473097 | |
Gastrointestinal health treatments | When indicated, improvement in digestion and assimilation of macro- and micronutrients was encouraged through the use of digestive enzymes, probiotics, herb-based and supplemental anti-inflammatories (curcumin, pro-resolvins), gut healing nutrients (e.g., aloe, deglycyrrhizinated licorice, glutamine), gut immune suppor... | PMC10473097 | ||
Systemic inflammation treatments | inflammation, infections | INFLAMMATION, INFECTIONS | Systemic inflammation was treated by reducing causes of inflammation, including toxin reduction, treatment of infections, dietary changes, exercise, omega-3 s, and additional dietary supplementation (e.g., curcumin, glutathione, B-vitamins, vitamin C, alpha-lipoic acid). | PMC10473097 |
Sleep treatments | SLEEP APNEA | Sleep hygiene was supported and tracked using a Garmin Vivo Smart 4 to measure hours and quality of sleep per night, plus oxygen saturation. All participants with O2 saturation levels falling below 85% during sleep were referred to sleep medicine for further evaluation and treatment of potential sleep apnea. Supplement... | PMC10473097 | |
Traumatic brain injury (TBI) treatments | stroke, traumatic brain injuries | STROKE | Those with a history of traumatic brain injuries or stroke were provided oral supplemental phosphatidylcholine, phosphatidylserine, omega-3’s, methyl-B12, and intravenous nicotinamide adenine dinucleotide (i.e., NAD+). | PMC10473097 |
Hormone treatments | Bio-identical hormone replacement and/or herbal hormonal support was initiated for participants with laboratory confirmed reduction in hormone levels [ | PMC10473097 | ||
Chronic infection treatments | P., cognitive decline, Herpetic, tick-borne infections | CHRONIC INFECTIONS, POSITIVE | Participants with recurrent or chronic infections associated with cognitive decline were treated. Herpetic outbreaks were prevented with lysine supplementation and Valacyclovir or Acyclovir, to be used at the first sign of prodrome. Positive tick-borne infections were treated with herbal antimicrobials (e.g., berberine... | PMC10473097 |
Outcome measures | The primary outcome of the study was changes in cognitive scores. Feasibility was qualitatively assessed. Study visits at baseline, month one, month 3, month 6, and month 12 included the following assessments, conducted by clinical research staff: | PMC10473097 | ||
Cognitive function testing (primary outcome) | cognitive domains— | BRAIN | The Cambridge Brain Sciences (CBS) assessments were used as the primary measure of cognition throughout the study. The CBS cognitive battery is a validated suite of 12 individual assessments designed to measure function in four cognitive domains— Memory, Reasoning, Verbal Ability, and Concentration. Each domain is asse... | PMC10473097 |
Montreal Cognitive Assessment (MoCA) | The MoCA is a brief, single page, valid and reliable 30-point screening test widely used clinically to assess and screen cognitive status [ | PMC10473097 | ||
Adverse events | ADVERSE EVENTS, ADVERSE EVENT, ADVERSE EVENT, ADVERSE EVENT | Adverse events were collected via a standardized adverse events questionnaire at each study and clinical visit, and participants were encouraged to contact study staff between study visits if adverse events occurred. These were tracked in an Adverse Events Log, and any unanticipated and/or severe adverse events were re... | PMC10473097 | |
Statistical analysis | In this uncontrolled study, before and after differences between baseline and endpoint values were calculated. The six-month endpoint was the primary endpoint of the study. An alpha threshold of Standardized individual scores from each CBS test (12 individual tests total) were transformed into four domain scores (Conce... | PMC10473097 | ||
DISCUSSION | Alzheimer’s disease, cognitive decline, dementia, cognitive impairment | As a proof-of-concept trial aimed at implementing a complex, multimodal, individualized medicine care plan in a sample of people with cognitive decline, the intervention demonstrated success in feasibility, thus supporting a larger, controlled, multi-site clinical trial. Additionally, results reported here corroborate ... | PMC10473097 | |
Supplementary Material | PMC10473097 | |||
Supplementary Table 1 | Click here for additional data file. | PMC10473097 | ||
Supplementary Table 2 | Click here for additional data file. | PMC10473097 | ||
Supplementary Table 3 | Click here for additional data file. | PMC10473097 | ||
Supplementary Table 4 | Click here for additional data file. | PMC10473097 | ||
ACKNOWLEDGMENTS | We are grateful to Nova Biomedical Corp, Quicksilver Scientific, Diagnostic Solutions Laboratory, DHA Labs, Xymogen, ReadiSorb, Pure Encapsulations, Douglas Labs, and Neurohacker Collective and Integrative Therapeutics for discounts and donations of labs and supplements. | PMC10473097 | ||
SUPPLEMENTARY MATERIAL | The supplementary material is available in the electronic version of this article: | PMC10473097 | ||
FUNDING | Funding was provided by an anonymous philanthropic donor.Mentorship on this research was supported by grant # K24AT011568 from the National Center for Complementary and Integrative Health of the National Institutes of Health. | PMC10473097 | ||
CONFLICT OF INTEREST | This manuscript is not under consideration by another journal, nor has it been published. Dr. Heather Sandison is the owner of a medical clinic and senior living facility. All the other authors have no conflict of interest to report. | PMC10473097 | ||
DATA AVAILABILITY | All data generated by our experiments will be shared in the form of publications, abstracts, and presentations. In the case of complex datasets, they will be available as supplementary data in publications or upon request by academic researchers. Where possible, primary data will be securely held for a period of ten ye... | PMC10473097 | ||
REFERENCES | PMC10473097 | |||
Background: | CM, pain | MECHANICAL LOW BACK PAIN | The study aimed to compare the effects of connective tissue massage (CTM) and classical massage (CM) in patients with chronic mechanical low back pain on pain and autonomic responses and to determine the most effective manual therapy method. | PMC10101266 |
Methods: | Oswestry disability, CM, pain | MECHANICAL LOW BACK PAIN, HEART | Seventy individuals with chronic mechanical low back pain were randomly divided into CTM (n = 35) and CM (n = 35) groups. The participants were given a 4-week treatment protocol consisting of a hot pack, exercise, and CTM or CM for 20 sessions. A visual analog scale was used to measure pain intensity. Heart rate, blood... | PMC10101266 |
Results: | Pain | Pain intensity was decreased in both groups ( | PMC10101266 | |
Conclusion: | CM, pain | The results of this study showed that massages were similar effect. The fact that CM is a frequently used technique in pain management and is as effective as CTM in autonomic responses will make it more preferred in the clinic. | PMC10101266 | |
1. Introduction | tumor, low back pain, headaches, fracture, muscle soreness, pain, infection, chronic neck pain, CM, drug abuse, Disability, disability | TUMOR, AUTONOMIC NERVOUS SYSTEM IMBALANCE, CHRONIC LOW BACK PAIN, FIBROMYALGIA, MECHANICAL LOW BACK PAIN, INFECTION, ADVERSE EFFECTS, INCREASED SLEEP, MECHANICAL LOW BACK PAIN, OSTEOPOROSIS | Mechanical low back pain is defined as a condition that causes tension, pain, or stiffness in the lumbar region without any specific cause (e.g., infection, tumor, osteoporosis, fracture, etc).Chronic low back pain negatively affects daily life and causes other problems in addition to pain. Disability due to pain can s... | PMC10101266 |
2. Methods | PMC10101266 | |||
2.1. Study design | This study was designed as a randomized, comparative, and mono-center study. The study was conducted in the Orthopedic Rehabilitation Unit of the Health Sciences Faculty of Eastern Mediterranean University between March 2019 and August 2021. The study was approved by the Health Ethics Committee (ETK00-2019-0177) and re... | PMC10101266 | ||
2.2. Participants | MECHANICAL LOW BACK PAIN | Patients diagnosed with chronic mechanical low back pain by orthopedics and traumatology doctors in local state hospital were included in the study. The G*Power software program (version 3.0; Kiel, Germany) was used to determine the required sample size for the study. Thus, a sample consisting of 54 participants (27 pe... | PMC10101266 | |
1.2.2. Inclusion and exclusion criteria | congenital malalignment, lower extremity inequality, numbness, pain, malignity | MECHANICAL LOW BACK PAIN, AXIAL SPONDYLOARTHROPATHY | The inclusion criteria were as follows: aged between 20 and 60 years, referred to a physiotherapy clinic, the presence of mechanical low back pain for more than 12 weeks, the absence of neurological problems originating from the lumbar region, and not participating in any physiotherapy and rehabilitation program in the... | PMC10101266 |
2.3. Randomization | CM | The patients were randomly assigned to one of the following 2 groups: CTM group (n = 35) and CM group (n = 35). Using the minimization method, the groups were made similar in terms of gender, age, and occupation. The participant flow chart is displayed in Figure The participant flow chart according to CONSORT is displa... | PMC10101266 | |
2.4. Interventions | CM | Patients were treated with CM or CTM after a hot pack application (20 minutes) to the lumbar region. In addition, all the participants were given lumbar strengthening and stretching exercises (Table Exercise program. | PMC10101266 | |
1.2.4. Connective tissue massage | hyperemia, strokes | HYPEREMIA, STROKES | The participant was seated on a stool with the entire back and sacral region open, hip and knee flexed at 90°, and feet on the ground during the treatment. While sitting, it was ensured that the back of the individual was straight and their hands supported the thighs for slight loosening of the connective tissue. CTM w... | PMC10101266 |
2.2.4. Classical massage | CM | CM was applied to the lower and upper back regions in the prone position. Massage oil was used as an intermediate. After general stroking to the entire back, stroking and kneading were applied to the erector spine, latissimus dorsi, and gluteus maximus muscles in the lower back. An upper back massage was performed afte... | PMC10101266 | |
2.5. Outcome measures | pain | All the outcomes were measured by the same physiotherapist the day before the first treatment session, the day after the completion of all treatments, and at the end of the 6-week follow-up. In addition, pain intensity was measured at the end of the 5 | PMC10101266 | |
1.2.5. Primary outcome measure | PMC10101266 | |||
1.2.5.1. Pain intensity | pain | A visual analog scale (VAS) was used to measure pain intensity. | PMC10101266 | |
2.2.5. Secondary outcome measures | PMC10101266 | |||
2.1.2.5. Autonomic functions | CM | BLOOD | Blood pressure, heart rate, and peripheral and local skin temperature changes were measured to evaluate the possible effects of CM and CTM on the autonomic responses.The blood pressure measurements were taken using a Erka Switch model manual sphygmomanometer. For the measurement, the participants were seated in a chair... | PMC10101266 |
2.6. Disability | Oswestry disability, disability | The Oswestry disability index (ODI) was used to evaluate the disability of the individuals. | PMC10101266 | |
2.7. Health-related quality of life | The short form 36 (SF-36) was used to assess health-related quality of life. | PMC10101266 | ||
2.8. Sleep quality | The Pittsburgh sleep quality index (PSQI) was used to determine sleep quality. PSQI is the preferred index in clinical and research studies. | PMC10101266 | ||
2.9. Statistical analysis | The obtained data were evaluated with the SPSS Version 22.0 program (SPSS Inc., Chicago, IL). The level of significance was accepted as | PMC10101266 | ||
3. Results | CM | The demographic information’s of the groups were similar (Table Comparisons of demographic information of individuals.BMI = body mass index, CM = classical massage, CTM = connective tissue massage. Mann–Whitney Chi-square test. | PMC10101266 | |
3.1. Pain intensity | CM, pain | When the time-dependent changes in the intensity of pain were analyzed, it was found that both treatments provided significant improvements (Table Comparison of pain intensity of the groups.Bold indicates significant values.CM = classical massage, CTM = connective tissue massage, VAS = visual analog scale. Mann–Whitney... | PMC10101266 | |
3.2. Autonomic functions | CM | When the time-dependent changes in the autonomic functions were analyzed, it was found that both treatments provided significant increases in right peripheral temperatures. Besides, it was found that there was a significant increase in left peripheral temperature in the CTM group (Table Comparisons of autonomic functio... | PMC10101266 | |
3.3. Disability | disability, CM | When the time-dependent changes in the disability were analyzed, it was found that both treatments provided significant improvements (Table Comparisons of disability, sleep quality, and health-related quality of life.Bold indicates significant values.CM = classical massage, CTM = connective tissue massage, NT = not tes... | PMC10101266 | |
3.4. Sleep quality | daytime sleep dysfunction, sleep disturbance, CM | When the time-dependent changes in the PSQI were analyzed, it was found that all subcategories (without the sleep medication) provided significant improvements in the CTM group (Table In the CM group, it was found that the sleep duration, sleep disturbance, and daytime sleep dysfunction subcategories provided significa... | PMC10101266 | |
3.5. Health-related quality of life | CM | When the time-dependent changes in the SF-36 results were analyzed, it was found that all categories provided significant improvements in the CTM group (Table There were statistically significant improvements in the CTM group for posttreatment and at the end of the 6-week follow-up physical functioning (posttreatment T... | PMC10101266 |
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