Nestor D. Tomycz

Deep brain stimulation for obesity—from theoretical foundations to designing the first human pilot study

Obesity is perhaps an evolutionary consequence of a species reared with intermittent caloric reward. Humans are hardwired to enjoy food, and our bodies voraciously extract and store energy from food as if each meal was the last. As an amalgam of behavioral and metabolic disturbance, obesity is an attractive target for deep brain stimulation (DBS) since neuromodulation may be able to influence both eating behavior and metabolism. The current pandemic proportions of obesity combined with the failures and morbidity of modern treatments remain the impetus behind the application of DBS to this complex disease. We review the rationale and scientific foundations for obesity DBS and explain how this preclinical evidence has helped sculpt the design of the first human pilot study.

Pursuing new targets and indications for deep brain stimulation: considerations for device-related clinical research in the United States.

DBS surgical research is particularly challenging since the FDA has classified DBS as a class III or “significant risk device.” To study novel targets or indications for a “significant risk device,” an investigator must obtain both FDA and institutional review board (IRB) approval. We believe that investigators should be better informed about the barriers surrounding medical device research and we would like to provide a roadmap for conducting investigational DBS surgery in humans.

Fentanyl Initiated Polymers Prepared by ATRP for Targeted Delivery

The targeted delivery of polymers to neurons is a challenging yet important goal for polymer based drug delivery. We prepared a fentanyl based atom transfer radical polymerization (ATRP) initiator to target the Mu opioid receptor (MOR) for neuronal targeting. We incorporated our recently discovered rigid acrylate linking group into the initiator to retain a high degree of binding to the MOR and grafted random or block copolymers of poly(oligo(ethylene oxide) methacrylate)-block-(glycidyl methacrylate). Trifluoroethanol promoted amine ring opening of the glycidyl methacrylate was used for post-polymerization modification of the fentanyl initiated polymers to attach a near-infrared fluorescent dye (ADS790WS) or to build a targeted siRNA delivery system via modification with secondary amines. We examined the biocompatibility, cellular internalization, and siRNA binding properties of our polymer library in a green fluorescent protein expressing SY SH5Y neuroblastoma cell-line.

Spinal Cord Stimulator Explantation: Motives for Removal of Surgically Placed Paddle Systems

Despite requiring successful trials prior to implantation, spinal cord stimulation (SCS) systems for pain are often later removed. Removing surgically implanted hardware subjects patients to the risks and discomfort of a second surgery, threatens the cost‐effectiveness of SCS, and limits the perceived durability of SCS technology for pain problems.

Synthesis and biological evaluation of fentanyl acrylic derivatives

The synthesis of novel fentanyl acrylate derivatives via bromo-fentanyl using Heck coupling is described. The synthesis is concise and represents an efficient and useful method for functionalizing fentanyl for medicinal chemistry investigations. The agonistic and analgesic activities are evaluated by Mu opioid receptor activation and hot plate assays in mice.

Extended-release of opioids using fentanyl-based polymeric nanoparticles for enhanced pain management

Opioid receptor agonists form the backbone of pharmacological pain management. The use of these drugs through the current delivery routes poses significant health risks, including abuse, addiction, respiratory depression, and death. Those risks can be alleviated through controlled release of opioids at therapeutic levels for prolonged periods. Biodegradable polymeric nanoparticles (NPs) have been utilized as controlled drug delivery vehicles due to their unique ability of presenting different molecules of interest at their surfaces. In this study, we focus on extended-release of the synthetic opioid fentanyl analogs for improved pain management. To this end, we report the formulation of fentanyl-bearing polylactide and polyglicolide NPs (Fen-PLA/PLGA NPs) with controlled size, surface features, and antinociceptive properties. Biocompatible Fen-PLA/PLGA NPs were formulated through opioid initiators Fen-OH and Fen-Ary-EtOH, to prepare opioid chain-end functional biodegradable polymers. The results demonstrate that a single subcutaneous dose of the prepared NPs delivers therapeutically relevant doses for up to six days in a mouse model of acute nociception without unwanted burst-release. To further our aim of precise administration of the novel opioid delivery systems into skin tissue, we envisioned and fabricated dissolvable microneedle arrays (MNAs) that integrate the formulated NPs at their tips. Our novel biohybrids, which can be delivered precisely and minimally-invasively using dissolvable MNAs, may be utilized to formulate opioids towards preventing overdose and abuse.

Craniotomy for subdural hematoma after deep brain stimulation surgery: Outcomes and satisfaction in a case series of two patients

OBJECTIVE To determine whether salvage of DBS hardware is beneficial for Parkinsons Disease (PD) patients by looking at follow-up patients outcomes and satisfaction after their craniotomy operation. PATIENTS AND METHODS This was a retrospective review of a prospective, single-center deep brain stimulation (DBS) database between 2002-2016 identifying patients with PD who developed subdural hematomas (SDH) due to trauma after their DBS surgery. Of the 636 DBS cases that were performed, 3 PD-DBS patients with significant traumatic SDH managed via craniotomy were identified. Out of these 3 patients, only 2 permitted outcome analysis. At follow-up, functional and neurologic status, UPDRS motor score, and overall satisfaction with DBS were assessed. RESULTS Two patients were followed for a period of 10 and 9 months. At last follow-up, the DBS settings in patient 1 increased from a stimulation amplitude of 3.5 V to 4.5 V on the right and 3.3 V to 6.0 V on the left with an increase in the pulse width as well (70-80 ms and 80-140 ms on the right and left, respectively). Stimulation frequency remained 160 Hz on the right while increasing from 145 to 160 Hz on the left. Patient 2 experienced an increase in stimulation amplitude from 4.5 V to 4.8 V on the right while remaining the same on the left. Pulse width increased from 60 to 70 ms bilaterally as well as the frequency (160-185 Hz bilaterally). Despite craniotomy, both patients experienced substantial improvement in UPDRS motor score with DBS at last follow-up (53-25 and 20-17 for patient 1 and 2, respectively). At last follow-up, CT imaging provided evidence of complete SDH resolution with no persistent hemorrhage, mass effect or any obvious lead displacement. Patients expressed satisfaction with DBS and affirmed that they would undergo surgery again for the same outcome. CONCLUSION Patients with PD are at higher risk for falls and may experience an increased risk of falling associated with SDH in the post-operative period after DBS implantation. Despite brain shift from SDH potentially distorting DBS leads, DBS implants still provided significant benefit in patients requiring craniotomy for SDH and patient satisfaction with DBS remained high. Salvage of DBS hardware is recommended since significant symptomatic improvement with DBS programming may still be attainable even in the setting of emergent craniotomy for SDH.

High Thoracic Disc Herniation Causing Horner Syndrome with the Intraoperative Finding of Conjoined Nerve Root Compression

Case: A 29-year-old man presented with right medial arm pain with paresthesia, as well as right-sided ptosis, miosis, and anhidrosis. Magnetic resonance imaging revealed a right paracentral disc herniation at the T1-T2 level. The patient underwent a hemilaminectomy with a medial facetectomy through a posterolateral approach to the T1-T2 disc space, followed by a discectomy. Intraoperative findings were notable for a conjoined nerve root. Conclusion: Although high thoracic disc herniation is rare, its diagnosis should be considered when patients present with radicular arm pain and Horner syndrome. A high index of suspicion should be maintained for nerve root anomalies to limit iatrogenic injury and to ensure successful decompression.

The proposed use of cervical spinal cord stimulation for the treatment and prevention of cognitive decline in dementias and neurodegenerative disorders

Cervical spinal cord stimulation is a well-established treatment for intractable neuropathic upper extremity pain. More than 20years ago it was demonstrated that cervical spinal cord stimulation could engender an increase in cerebral blood flow. Cerebral blood flow has been shown to be decreased in many patients with dementia and in various neurodegenerative disorders such as Alzheimers disease and Parkinsons disease. Furthermore, there is evidence that reduced cerebral blood flow worsens neurodegenerative disease and may also predict which patients progress from mild cognitive impairment to full blown Alzheimers disease. Thus, the identification of decreased cerebral blood flow in patients with early cognitive problems may offer clinicians a window of opportunity to intervene and prevent further brain damage. Further evidence that supports augmenting cerebral blood flow as an effective strategy for preventing and treating cognitive brain dysfunction comes from experimental studies with omental transposition. The author proposes cervical spinal cord stimulation as a titratable, programmable extracranial neuromodulation technique to increase cerebral blood flow for the purposes of improving cognitive function and preventing cognitive deterioration in patients with dementias and neurodegenerative disorders.

Traumatic Conus Medullaris Syndrome

Case: A twenty-six-year-old man was diagnosed with conus medullaris syndrome (CMS) after sustaining a traumatic L1 burst fracture. Surgical decompression and stabilization was performed within ninety-six hours of admission; postoperatively, normal bladder function rapidly returned. Conclusion: CMS is difficult to diagnose because of the clinically variable presentation. There is no consensus regarding the natural history of conus medullaris injury or regarding the necessity, approach, or timing for decompression. Higher-level evidence is needed to guide treatment for acute traumatic CMS.