Chronic bisphenol A exposure induces temporal neurobehavioral transformation and augmented chromatin condensation in the periventricular gray zone of zebrafish brain.

Bisphenol A (BPA) is an industrial synthetic chemical that is extensively used for manufacturing polycarbonate plastics and epoxy resins. However, there is limited literature on BPA-induced temporal neurobehavioral transformation and oxidative stress-mediated neurodegeneration in the subtle region of the zebrafish brain. Consequently, an investigational setup was prepared to study the temporal response to duration-dependent BPA exposure on neurobehavioral, oxidative stress, and neurodegeneration in zebrafish. Zebrafish were divided into five groups: naïve, control, 7 days (BPA7D), 14 days (BPA14D), and 21 days (BPA21D). Our findings indicated that chronic waterborne exposure to BPA substantially altered the light/dark preference and bottom-dwelling behavior of zebrafish in the BPA14D, and BPA21D groups compared with naïve and control groups. Biochemical studies revealed that there was a significant downregulation in the cellular level of small-molecule antioxidants evidenced by reduced glutathione (GSH) and activity of antioxidant enzymes of glutathione biosynthesis in a duration-dependent manner after exposure to BPA. However, exposure to BPA for 7 days did not induce substantial alteration in biochemical parameters, such as GSH level, protein carbonylation, and superoxide dismutase activity, although the neurobehavioral responses expressively differed from those of the naïve and control groups. Moreover, our histopathological observation also indicated a temporal augmentation in chromatin condensation in the periventricular gray zone (PGZ) of the zebrafish brain after chronic exposure to BPA. The overall outcomes of the present study indicated that the transformed neurobehavioral phenotypes in zebrafish are a consequence of BPA-induced oxidative stress and PGZ neurodegeneration and clearly show a temporal transformation under BPA exposure.

Clinical applications of neurochemical and electrophysiological measurements for closed-loop neurostimulation.

The development of closed-loop deep brain stimulation (DBS) systems represents a significant opportunity for innovation in the clinical application of neurostimulation therapies. Despite the highly dynamic nature of neurological diseases, open-loop DBS applications are incapable of modifying parameters in real time to react to fluctuations in disease states. Thus, current practice for the designation of stimulation parameters, such as duration, amplitude, and pulse frequency, is an algorithmic process. Ideal stimulation parameters are highly individualized and must reflect both the specific disease presentation and the unique pathophysiology presented by the individual. Stimulation parameters currently require a lengthy trial-and-error process to achieve the maximal therapeutic effect and can only be modified during clinical visits. The major impediment to the development of automated, adaptive closed-loop systems involves the selection of highly specific disease-related biomarkers to provide feedback for the stimulation platform. This review explores the disease relevance of neurochemical and electrophysiological biomarkers for the development of closed-loop neurostimulation technologies. Electrophysiological biomarkers, such as local field potentials, have been used to monitor disease states. Real-time measurement of neurochemical substances may be similarly useful for disease characterization. Thus, the introduction of measurable neurochemical analytes has significantly expanded biomarker options for feedback-sensitive neuromodulation systems. The potential use of biomarker monitoring to advance neurostimulation approaches for treatment of Parkinson's disease, essential tremor, epilepsy, Tourette syndrome, obsessive-compulsive disorder, chronic pain, and depression is examined. Further, challenges and advances in the development of closed-loop neurostimulation technology are reviewed, as well as opportunities for next-generation closed-loop platforms.

Deep brain stimulation of the dorsal anterior cingulate cortex for the treatment of chronic neuropathic pain.

Chronic neuropathic pain is estimated to affect 3%-4.5% of the worldwide population. It is associated with significant loss of productive time, withdrawal from the workforce, development of mood disorders such as depression and anxiety, and disruption of family and social life. Current medical therapeutics often fail to adequately treat chronic neuropathic pain. Deep brain stimulation (DBS) targeting subcortical structures such as the periaqueductal gray, the ventral posterior lateral and medial thalamic nuclei, and the internal capsule has been investigated for the relief of refractory neuropathic pain over the past 3 decades. Recent work has identified the dorsal anterior cingulate cortex (dACC) as a new potential neuromodulation target given its central role in cognitive and affective processing. In this review, the authors briefly discuss the history of DBS for chronic neuropathic pain in the United States and present evidence supporting dACC DBS for this indication. They review existent literature on dACC DBS and summarize important findings from imaging and neurophysiological studies supporting a central role for the dACC in the processing of chronic neuropathic pain. The available neurophysiological and empirical clinical evidence suggests that dACC DBS is a viable therapeutic option for the treatment of chronic neuropathic pain and warrants further investigation.

Periaqueductal/periventricular gray deep brain stimulation for the treatment of neuropathic facial pain.

Background: The Periaqueductal gray (PAG) and the periventricular gray (PVG) are the anatomical targets for deep brain stimulation (DBS) to treat severe, refractory neuropathic pain. Methods: Seven (four female and three male) patients were qualified for PAG/PVG DBS because of neuropathic facial pain. Frame-based unilateral implantations of DBS were conducted according to indirect planning of the PAG/PVG, contralateral to reported pain (3389, Activa SC 37603, Medtronic). The efficacy of PAG/PVG DBS on pain was measured with Numeric Pain Rating Scale (NRS) and Neuropathic Pain Symptom Inventory (NPSI) before surgery and 3, 12, and 24 months after surgery. Results: The mean age of the group at the implantation was 43.7 years (range: 28-62; SD: 12.13). The mean duration of pain varied from 2 to 12 years (mean: 7.3; SD: 4.11). Five patients suffered from left-sided facial pain and two suffered right-sided facial pain. The etiology of pain among four patients was connected to ischemic brain stroke and in one patient to cerebral hemorrhagic stroke. Patients did not suffer from any other chronic medical condition The beginnings of ailments among two patients were related to craniofacial injury. NRS decreased by 54% at the 3 months follow-up. The efficacy of the treatment measured with mean NRS decreased at one-year follow-up to 48% and to 45% at 24 months follow-up. The efficacy of the treatment measured with NPSI decreased from 0.27 to 0.17 at 2 years follow-up (mean reduction by 38%). The most significant improvement was recorded in the first section of NPSI (Q1: burning- reduced by 53%). The records of the last section (number five) of the NPSI (paresthesia/dysesthesia- Q11/Q12) have shown aggravation of those symptoms by 10% at the two-years follow-up. No surgery- or hardware-related complications were reported in the group. Transient adverse effects related to the stimulation were eliminated during the programming sessions. Conclusion: PAG/PVG DBS is an effective and safe method of treatment of medically refractory neuropathic facial pain. The effectiveness of the treatment tends to decrease at 2 years follow-up. The clinical symptoms which tend to respond the best is burning pain. Symptoms like paresthesia and dysesthesia might increase after DBS treatment, even without active stimulation.

Semi-quantitative analysis of periventricular gray-white matter ratio on CT in patients with idiopathic normal pressure hydrocephalus.

To investigate alterations in the periventricular gray-white matter ratio (GWR) on computed tomography (CT) in patients with idiopathic normal pressure hydrocephalus (INPH), a total of 140 patients with INPH and 52 age-and sex-matched controls were included by using Japanese guidelines published in 2021: possible, probable, and definite INPH for a retrospective case-control study. The non-enhanced brain CT was reviewed, and the Hounsfield unit (HU) was semi-quantitatively measured using the region of interest (ROI). The size (40 mm2) and location of the ROI were standardized within the periventricular white matter (WM) and thalamus. Bilateral anterior (ant) and posterior (post) periventricular WMs were measured using the ROI. The GWR was calculated using the HU on ROI at the thalamus and ant or post-periventricular WMs: GWR = HU at thalamus/HU at periventricular WM. There was a significant difference in the GWRs between patients with INPH and controls at the group level. A significant difference in the GWRs was found only in the ant part of the periventricular area; the bilateral GWRs ant were significantly higher in patients with INPH than in controls (p < 0.0001 with multiple corrections). The ROC analysis clearly showed a cut-off value of GWRs (>1.17) for diagnosing INPH. The diagnostic accuracy was satisfactory: >90% with specificity and>93% with a positive predictive value. The sensitivity and negative predictive value (NPV) were acceptable: >57% with sensitivity and>50% NPV. The GWR ant on CT could be a useful and reliable diagnostic tool in patients with INPH.

Deep Brain Stimulation for Chronic Pain.

Deep brain stimulation (DBS) is a neurosurgical intervention well known for the treatment of movement disorders as well as epilepsy, Tourette syndrome, and obsessive-compulsive disorders. DBS was pioneered in the 1950s, however, as a tool for treating facial pain, phantom limb pain, post-stroke pain, and brachial plexus pain among other disease states. Various anatomic targets exist, including the sensory thalamus (ventral posterior lateral and ventral posterior medial), the periaqueductal gray and periventricular gray matter, and the anterior cingulate cortex.

Deep Brain Stimulation and Motor Cortex Stimulation for Chronic Pain.

Deep brain stimulation (DBS) and Motor Cortex stimulation (MCS) have been used for control of chronic pain. Chronic pain of any origin is complex and difficult to treat. Stimulation of various areas in brain-like sensory thalamus, medial nuclei of thalamus including centro-lateral nucleus of thalamus (CL), periaqueductal gray, periventricular gray, nucleus accumbence and motor cortex provides partial relief in properly selected patients. This article reviews the pain pathways, theories of pain, targets for DBS and rationale of DBS and MCS. It also discusses the patient selection, technical details of each target.

Contemporary concepts of pain surgery.

Pain surgery is one of the historic foundations of neurological surgery. The authors present a review of contemporary concepts in surgical pain management, with reference to past successes and failures, what has been learned as a subspecialty over the past 50 years, as well as a vision for current and future practice. This subspecialty confronts problems of cancer pain, nociceptive pain, and neuropathic pain. For noncancer pain, ablative procedures such as dorsal root entry zone lesions and rhizolysis for trigeminal neuralgia (TN) should continue to be practiced. Other procedures, such as medial thalamotomy, have not been proven effective and require continued study. Dorsal rhizotomy, dorsal root ganglionectomy, and neurotomy should probably be abandoned. For cancer pain, cordotomy is an important and underutilized method for pain control. Intrathecal opiate administration via an implantable system remains an important option for cancer pain management. While there are encouraging results in small case series, cingulotomy, hypophysectomy, and mesencephalotomy deserve further detailed analysis. Electrical neuromodulation is a rapidly changing discipline, and new methods such as high-frequency spinal cord stimulation (SCS), burst SCS, and dorsal root ganglion stimulation may or may not prove to be more effective than conventional SCS. Despite a history of failure, deep brain stimulation for pain may yet prove to be an effective therapy for specific pain conditions. Peripheral nerve stimulation for conditions such as occipital neuralgia and trigeminal neuropathic pain remains an option, although the quality of outcomes data is a challenge to these applications. Based on the evidence, motor cortex stimulation should be abandoned. TN is a mainstay of the surgical treatment of pain, particularly as new evidence and insights into TN emerge. Pain surgery will continue to build on this heritage, and restorative procedures will likely find a role in the armamentarium. The challenge for the future will be to acquire higher-level evidence to support the practice of surgical pain management.

Current and future directions of deep brain stimulation for neurological and psychiatric disorders.

Deep brain stimulation (DBS) has evolved considerably over the past 4 decades. Although it has primarily been used to treat movement disorders such as Parkinson's disease, essential tremor, and dystonia, recently it has been approved to treat obsessive-compulsive disorder and epilepsy. Novel potential indications in both neurological and psychiatric disorders are undergoing active study. There have been significant advances in DBS technology, including preoperative and intraoperative imaging, surgical approaches and techniques, and device improvements. In addition to providing significant clinical benefits and improving quality of life, DBS has also increased the understanding of human electrophysiology and network interactions. Despite the value of DBS, future developments should be aimed at developing less invasive techniques and attaining not just symptom improvement but curative disease modification.

3-Tesla MRI in patients with fully implanted deep brain stimulation devices: a preliminary study in 10 patients.

OBJECTIVE The aim of this study was to evaluate the safety of 3-T MRI in patients with implanted deep brain stimulation (DBS) systems. METHODS This study was performed in 2 phases. In an initial phantom study, a Lucite phantom filled with tissue-mimicking gel was assembled. The system was equipped with a single DBS electrode connected to an internal pulse generator. The tip of the electrode was coupled to a fiber optic thermometer with a temperature resolution of 0.1°C. Both anatomical (T1- and T2-weighted) and functional MRI sequences were tested. A temperature change within 2°C from baseline was considered safe. After findings from the phantom study suggested safety, 10 patients with implanted DBS systems targeting various brain areas provided informed consent and underwent 3-T MRI using the same imaging sequences. Detailed neurological evaluations and internal pulse generator interrogations were performed before and after imaging. RESULTS During phantom testing, the maximum temperature increase was registered using the T2-weighted sequence. The maximal temperature changes at the tip of the DBS electrode were < 1°C for all sequences tested. In all patients, adequate images were obtained with structural imaging, although a significant artifact from lead connectors interfered with functional imaging quality. No heating, warmth, or adverse neurological effects were observed. CONCLUSIONS To the authors' knowledge, this was the first study to assess the clinical safety of 3-T MRI in patients with a fully implanted DBS system (electrodes, extensions, and pulse generator). It provided preliminary data that will allow further examination and assessment of the safety of 3-T imaging studies in patients with implanted DBS systems. The authors cannot advocate widespread use of this type of imaging in patients with DBS implants until more safety data are obtained.

The midbrain central gray best suppresses chronic pain with electrical stimulation at very low pulse rates in two human cases.

Deep brain stimulation in the midbrain׳s central gray can relieve neuropathic pain in man, but for unclear reasons sometimes fails intraoperatively or in early weeks. Here we describe continuous bilateral stimulation in the central gray of two subjects with longstanding, severe neuropathic pain from spinal cord injury. Stimulation parameters were recursively adjusted over many weeks to optimize analgesia while minimizing adverse effects. In early weeks, adjustments were made in periodic office visits; subjects later selected ad libitum at home among several blinded choices while rating pain twice daily. Both subjects received significantly better pain relief when stimulus pulse rates were low. The best relief occurred with 2 Hz cycled on for 1s and off for 2s. After inferior parameters were set, pain typically climbed slowly over 1-2 days; superior parameters led to both slow and fast improvements. Over many weeks of stimulation at low pulse rates, both subjects experienced significantly less interference from pain with sleep. One subject, with major pain relief, also showed less interference with social/recreational ability and mood; the other subject, despite minor pain relief, experienced a significantly positive global impression of change. Oscillopsia, the only observed complication of stimulation, disappeared at low mean pulse rates (≤ 3/s). These subjects׳ responses are not likely to be unique even if they are uncommon. Thus daily or more frequent pain assessment, combined with slower periodic adjustment of stimulation parameters that incorporate mean pulse rates about one per second, will likely improve success with this treatment.

Effects of Deep Brain Stimulation on Autonomic Function.

Over the course of the development of deep brain stimulation (DBS) into a well-established therapy for Parkinson's disease, essential tremor, and dystonia, its utility as a potential treatment for autonomic dysfunction has emerged. Dysfunction of autonomic processes is common in neurological diseases. Depending on the specific target in the brain, DBS has been shown to raise or lower blood pressure, normalize the baroreflex, to alter the caliber of bronchioles, and eliminate hyperhidrosis, all through modulation of the sympathetic nervous system. It has also been shown to improve cortical control of the bladder, directly induce or inhibit the micturition reflex, and to improve deglutition and gastric emptying. In this review, we will attempt to summarize the relevant available studies describing these effects of DBS on autonomic function, which vary greatly in character and magnitude with respect to stimulation target.

Multi-target neurostimulation for adequate long-term relief of neuropathic and nociceptive chronic pain components.

Successful treatment of chronic pain for patients with failed back surgery syndrome can be extremely complicated. These patients require careful and individualized clinical assessment, as they often present with mixed pain syndromes that involve both neuropathic and nociceptive components. The distinct types of pain involved in such cases may require combined treatments from individual interventions that are analgesically independent and specific for each type of pain involved. Neuromodulation by electric stimulation at appropriately chosen targets and combinations may be an important option to consider for such patients. We present a case of combined debilitating axial nociceptive spinal pain and bilateral neuropathic leg pain in a patient after 14 failed back operations. A combination of spinal cord stimulation (SCS) and deep brain stimulation in the periventricular gray (PVG) have successfully provided the patient with complete relief of both components of his chronic pain condition, after all other pain management options had been exhausted. By alternating activation of each implanted stimulator separately and in conjunction, we were able to demonstrate a clinically independent analgesic character for each stimulation system, each specific to a particular type of pain. The SCS provided complete relief of the neuropathic pain component, without affecting the nociceptive component at all. The PVG stimulation provided complete relief of the nociceptive component, without affecting the neuropathic component at all. In combination, there was complete relief of the total chronic pain condition. There appeared to be no overlapping or synergistic effect between the two neuromodulation systems in the patient. The patient has had prolonged complete relief from his chronic pain condition with the combined neuromodulation intervention over 22 years of follow-up.

Deep brain stimulation for pain.

Deep brain stimulation (DBS) is a neurosurgical intervention whose efficacy, safety, and utility have been shown in the treatment of movement disorders. For the treatment of chronic pain refractory to medical therapies, many prospective case series have been reported, but few have published findings from patients treated during the past decade using current standards of neuroimaging and stimulator technology. We summarize the history, science, selection, assessment, surgery, and personal clinical experience of DBS of the ventral posterior thalamus, periventricular/periaqueductal gray matter, and, latterly, the rostral anterior cingulate cortex (Cg24) in 100 patients treated now at two centers (John Radcliffe Hospital, Oxford, UK, and Hospital de São João, Porto, Portugal) over 12 years. Several experienced centers continue DBS for chronic pain with success in selected patients, in particular those with pain after amputation, brachial plexus injury, stroke, and cephalalgias including anesthesia dolorosa. Other successes include pain after multiple sclerosis and spine injury. Somatotopic coverage during awake surgery is important in our technique, with cingulate DBS considered for whole-body pain or after unsuccessful DBS of other targets. Findings discussed from neuroimaging modalities, invasive neurophysiological insights from local field potential recording, and autonomic assessments may translate into improved patient selection and enhanced efficacy, encouraging larger clinical trials.