Back to table of contents Previous article Next article Case ReportsNo AccessElimination of Refractory Aggression and Self-Injury With Contingent Skin ShockNathan Blenkush, Ph.D., and Miles Cunningham, M.D., Ph.D.Nathan Blenkush, Ph.D., and Miles Cunningham, M.D., Ph.D.Published Online:14 Feb 2023https://doi.org/10.1176/appi.neuropsych.21020049AboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail View article Access content To read the fulltext, please use one of the options below to sign in or purchase access. Personal login Institutional Login Sign in via OpenAthens Register for access Purchase Save for later Item saved, go to cart PPV Articles - Journal of Neuropsychiatry and Clinical Neurosciences $35.00 Add to cart PPV Articles - Journal of Neuropsychiatry and Clinical Neurosciences Checkout Please login/register if you wish to pair your device and check access availability. Not a subscriber? Subscribe Now / Learn More PsychiatryOnline subscription options offer access to the DSM-5 library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development. Need more help? PsychiatryOnline Customer Service may be reached by emailing [email protected] or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.). FiguresReferencesCited byDetailsCited byContingent Electric Skin Shock: An Empirical or Ideological Issue?26 June 2023 | Perspectives on Behavior Science, Vol. 46, No. 2 Volume 35Issue 3 Summer 2023Pages 264-268 Metrics KeywordsSelf-MutilationViolence/AggressionSelf-InjuryTreatment RefractorySkin ShockPDF download History Received 22 February 2021 Revised 24 March 2022 Accepted 27 November 2022 Published online 14 February 2023 Published in print 1 July 2023

Zolpidem is a clinically effective hypnotic medication for treating chronic insomnia. In the last decade, there has been increasing documentation of altered consciousness and behavioral changes following zolpidem administration. This report presents a case of a probable zolpidem induced suicide attempt and highlights similar studies of suicidal thoughts and behaviors of other patients that have taken the drug. We examine zolpidem and other treatments for insomnia, including the FDA approved hypnotics and frequently prescribed off-label medications, in terms of prescribing practices and adverse effects, especially altered consciousness and risk of suicide. Parallels are identified between the untoward activating side effects of zolpidem and its off-label use for patients in persistent vegetative states. We hypothesize that similar to the proposed mechanism in which the wakefulness promoted by zolpidem in vegetative patients is mediated by disruption of GABAergic tone in neurodormant brain regions, there may occur in patients with parasomnias interference of GABA activity in brain regions that maintain a high level of inhibitory regulation. Dosing recommendations are offered together with the FDA Safety Announcement addressing dose reductions for women due to possible carry-over effects the morning after ingesting zolpidem.

A small proportion of patients with intellectual disabilities (IDs) and/or autism spectrum disorder (ASD) exhibit extraordinarily dangerous self-injurious and assaultive behaviours that persist despite long-term multidisciplinary interventions. These uncontrolled behaviours result in physical and emotional trauma to the patients, care providers and family members. A graduated electronic decelerator (GED) is an aversive therapy device that has been shown to reduce the frequency of severe problem behaviours by 97%. Within a cohort of 173 patients, we have identified the four most common patterns of response: (1) on removal of GED, behaviours immediately return, and GED is reinstated; (2) GED is removed for periods of time (faded) and reinstated if and when behaviours return; (3) a low frequency of GED applications maintains very low rates of problem behaviours; and (4) GED is removed permanently after cessation of problem behaviours. GED is intended as a therapeutic option only for violent, treatment-resistant patients with ID and ASD.

Exposure to early-life adversity (ELA) increases the risk for psychopathologies associated with amygdala-prefrontal cortex (PFC) circuits. While sex differences in vulnerability have been identified with a clear need for individualized intervention strategies, the neurobiological substrates of ELA-attributable differences remain unknown due to a paucity of translational investigations taking both development and sex into account. Male and female rats exposed to maternal separation ELA were analyzed with anterograde tracing from basolateral amygdala (BLA) to PFC to identify sex-specific innervation trajectories through juvenility (PD28) and adolescence (PD38;PD48). Resting-state functional connectivity (rsFC) was assessed longitudinally (PD28;PD48) in a separate cohort. All measures were related to anxiety-like behavior. ELA-exposed rats showed precocial maturation of BLA-PFC innervation, with females affected earlier than males. ELA also disrupted maturation of female rsFC, with enduring relationships between rsFC and anxiety-like behavior. This study is the first providing both anatomical and functional evidence for sex- and experience-dependent corticolimbic development.

NSI-566 is a stable, primary adherent neural stem cell line derived from a single human fetal spinal cord and expanded epigenetically with no genetic modification. This cell line is being tested in clinical trials in the U.S. for treatment of amyotrophic lateral sclerosis and spinal cord injury. In a single-site, phase I study, we evaluated the feasibility and safety of NSI-566 transplantation for the treatment of hemiparesis due to chronic motor stroke and determined the maximum tolerated dose for future trials. Three cohorts (n = 3 per cohort) were transplanted with one-time intracerebral injections of 1.2 x 10(7), 2.4 x 10(7), or 7.2 x 10(7) cells. Immunosuppression therapy with tacrolimus was maintained for 28 days. All subjects had sustained chronic motor strokes, verified by magnetic resonance imaging (MRI), initiated between 5 and 24 months prior to surgery with modified Rankin Scores [MRSs] of 2, 3, or 4 and Fugl-Meyer Motor Scores of 55 or less. At the 12-month visit, the mean Fugl-Meyer Motor Score (FMMS, total score of 100) for the nine participants showed 16 points of improvement (p = .0078), the mean MRS showed 0.8 points of improvement (p = .031), and the mean National Institutes of Health Stroke Scale showed 3.1 points of improvement (p = .020). For six participants who were followed up for 24 months, these mean changes remained stable. The treatment was well tolerated at all doses. Longitudinal MRI studies showed evidence indicating cavity-filling by new neural tissue formation in all nine patients. Although this was a small, one-arm study of feasibility, the results are encouraging to warrant further studies. Stem Cells Translational Medicine 2019;8:999-1007

OBJECTIVE: This video article describes and illustrates the function and application of the intracerebral microinjection instrument (IMI). This newly developed technology allows delivery of therapeutic agents within the human brain in complex 3-dimensional arrays using a single pass or minimal overlying penetrations through brain tissue. METHODS: The IMI uses a delivery microcannula with a reduced diameter that minimizes local trauma and is capable of delivering precise volumes of therapeutic agents to discrete brain substructures. The IMI also permits simultaneous recording of neural activity during the delivery procedure, enabling extreme precision using electrophysiologic mapping. Surgical planning software designed specifically for the IMI enables strategic placement of multiple injections. RESULTS: This technology platform is presently being --A successfully to deliver therapeutic stem cells to restore function in stroke patients. CONCLUSIONS: Additional applications of the IMI include delivery of viral vectors for gene therapy, infusion of neurotrophic factors, targeted delivery of chemotherapeutic agents, and delivery of antiretroviral medications.

Adverse early experiences significantly alter behavioral and neural trajectories via aberrant brain maturation. Children with a history of early life stress (ELS) exhibit maladaptive behaviors and increased risk of mental illness later in life. Evidence in ELS-exposed humans identifies a role of atypical corticolimbic development; specifically, within amygdala-prefrontal cortex (PFC) circuits, and show precocially mature task-based corticolimbic functional connectivity (FC). However, the neurobiological substrates of such ELS-driven developmental changes remain unknown. Here, we identify putative neurobiological changes to determine the timeline of developmental perturbations following ELS in rats. Anterograde axonal tracing from basolateral amygdala (BLA) to pre- and infralimbic (PL, IL) PFC was quantified at postnatal days (PD)28, 38, and 48, along with anxiety-like behavior, in maternally separated (ELS) or control reared (CON) male and female rats. Resting state (rs)FC was assessed at PD28 and PD48 in a separate cohort. We report that ELS-exposed female rats show early maturation of BLA-PFC innervation at PD28, with ELS-related changes in males not appearing until PD38. ELS disrupted the maturation of rsFC from PD28 to PD48 in females, with enduring relationships between early rsFC and later anxiety-like behavior. Only transient ELS-related changes in rsFC were seen in male PL. Together, these data provide evidence that female rats may be more vulnerable to the effects of ELS via precocial BLA-PFC innervation, which may drive altered corticolimbic rsFC. These data also provide evidence that increased BLA-IL rsFC is associated with behavioral resiliency following ELS in female rats, providing mechanistic insight into the underlying etiology of adversity-induced vulnerability and resiliency.

GABAergic dysfunction in hippocampus, a key feature of schizophrenia (SZ), may contribute to cognitive impairment in this disorder. In stratum oriens (SO) of sector CA(3/2) of the human hippocampus, a network of genes involved in the regulation of glutamic acid decarboxylase GAD(67) has been identified. Several of the genes in this network including epigenetic factors histone deacetylase 1 (HDAC1) and death-associated protein 6 (DAXX), the GABAergic enzyme GAD(65) as well as the kainate receptor (KAR) subunits GluR6 and 7 show significant changes in expression in this area in SZ. We have tested whether HDAC1 and DAXX regulate GAD(67), GAD(65), or GluR in the intact rodent hippocampus. Stereotaxic injections of lentiviral vectors bearing shRNAi sequences for HDAC1 and DAXX were delivered into the SO of CA(3/2), followed by laser microdissection of individual transduced GABA neurons. Quantitative PCR (QPCR) analyses demonstrated that inhibition of HDAC1 and DAXX increased expression of GAD(67), GAD(65), and GluR6 mRNA. Inhibition of DAXX, but not HDAC1 resulted in a significant increase in GluR7 mRNA. Our data support the hypothesis that HDAC1 and DAXX play a central role in coordinating the expression of genes in the GAD(67) regulatory pathway in the SO of CA3/2.

Rodent brain atlases have traditionally been used to identify brain structures in three-dimensional space for a variety of stereotaxic procedures. As neuroscience becomes increasingly sophisticated, higher levels of precision and consistency are needed. Observations of various atlases currently in use across labs reveal numerous coordinate discrepancies. Here we provide examples of inconsistencies by comparing the coordinates of the boundaries of various brain structures across six atlas publications. We conclude that the coordinates determined by any particular atlas should be considered as only a first approximation of the actual target coordinates for the experimental animal for a particular study. Furthermore, the coordinates determined by one research team cannot be assumed to be universally applicable and accurate in other experimental settings. To optimize precision, we describe a simple protocol for the construction of a customized atlas that is specific to the surgical approach and to the species, gender, and age of the animal used in any given study.

OBJECTIVES:The ability to safely place viable intracerebral grafts of human-derived therapeutic stem cells in three-dimensional (3D) space was assessed in a porcine model of human stereotactic surgery using the Intracerebral Microinjection Instrument (IMI) compared to a conventional straight cannula.MATERIALS AND METHODS:Two groups of healthy minipigs received injections of the human stem cell line, NSI-566, into the right hemisphere and cell suspension carrier media into the left hemisphere. Group A received all injections using a straight, 21-gauge stainless steel cannula. Group B received all injections using the IMI, whereby radial distribution of injections was achieved via angular extension of a 196-micron diameter cannula from a single overlying penetration of the guide cannula. Each animal received six 20 µL intracerebral-injections within each hemisphere: three in a radial distribution, covering a 180° arc with each injection separated by a 60° arc distance, within both frontal cortex and basal ganglia. H&E and immunocytochemistry (HuNu and GFAP) were used to identify implanted cells and to assess tissue response.RESULTS:The presence of surviving cells in appropriate brain regions demonstrated that the IMI is capable of accurately delivering viable human-derived stem cells safely in a 3D array at predetermined sites within the pig brain. In addition, qualitative evaluation of the target tissue suggests efficient delivery with decreased surgical trauma.CONCLUSIONS:In contrast to traditional straight cannulas, the IMI enables the delivery of multiple precise cellular injection volumes in accurate 3D arrays. In this porcine large animal model of human neurosurgery, the IMI reduced surgical time and appeared to reduce neural trauma associated with multiple penetrations that would otherwise be required using a conventional straight delivery cannula.

Background: Deep brain stimulation (DBS) has been shown to be effective for parkinsonian symptoms poorly responsive to medications. DBS is typically well-tolerated, as are the maintenance battery changes. Here we describe an adverse event during a battery replacement procedure that caused rapid onset of severe depression.Case Presentation: The patient is a 58-year-old woman who was in a serious motor vehicle accident and sustained a concussion with loss of consciousness. Within weeks of the accident she began developing parkinsonian symptoms that progressively worsened over the subsequent 10 years. Responding poorly to medications, she received DBS, which controlled her movement symptoms. Five years after initiating DBS, during a routine battery change, an apparent electrical event occurred that triggered the rapid onset of severe depression. Anti-seizure and antidepressant medications were ineffective, and the patient was offered a course of electroconvulsive therapy (ECT), which resulted in complete reversal of her depressive episode.Conclusion: Parkinson's syndrome can be seen after a single closed head injury event. Post-traumatic parkinsonism is responsive to DBS; however, DBS has been associated with an infrequent occurrence of dramatic disruption in mood. ECT is a therapeutic option for patients who develop intractable depressive illness associated with DBS.

Seizure disorders debilitate more than 65,000,000 people worldwide, with temporal lobe epilepsy (TLE) being the most common form. Previous studies have shown that transplantation of GABA-releasing cells results in suppression of seizures in epileptic mice. Derivation of interneurons from human pluripotent stem cells (hPSCs) has been reported, pointing to clinical translation of quality-controlled human cell sources that can enhance inhibitory drive and restore host circuitry. In this study, we demonstrate that hPSC-derived maturing GABAergic interneurons (mGINs) migrate extensively and integrate into dysfunctional circuitry of the epileptic mouse brain. Using optogenetic approaches, we find that grafted mGINs generate inhibitory postsynaptic responses in host hippocampal neurons. Importantly, even before acquiring full electrophysiological maturation, grafted neurons were capable of suppressing seizures and ameliorating behavioral abnormalities such as cognitive deficits, aggressiveness, and hyperactivity. These results provide support for the potential of hPSC-derived mGIN for restorative cell therapy for epilepsy.

Temporal lobe epilepsy (TLE) has been modeled in mice using pilocarpine induction, with variable results depending on specific strains. To allow efficient xenotransplantation for the purpose of optimizing potential cell-based therapy of human TLE, we have determined the optimal dosing strategy to produce spontaneous recurring seizures in immunodeficient NodScid mice. Multiple 100 mg/kg injections of pilocarpine have been shown to be more effective than single 300-400 mg/kg injections for inducing spontaneous seizures in NodScid mice. Under our optimal conditions, 88.1 +/- 2.9% of the mice experienced status epilepticus (SE) with a survival rate of 61.8 +/- 5.9%. Surviving SE mice displayed spontaneous recurrent seizures at a frequency of 2.8 +/- 0.9 seizures/day for a duration of 41.1 +/- 3.5 s. The widely used method of a single injection of pilocarpine was significantly less efficient in inducing seizures in NodScid mice. Therefore, we have determined that a multiple injection "ramping up" of 100 mg/kg of pilocarpine is optimal for inducing TLE-like spontaneous seizures in NodScid mice. Using this method, mice with SE efficiently developed SRS and expressed mossy fiber sprouting, a signature histopathological feature of TLE. (C) 2014 Elsevier B.V. All rights reserved.

ABSTRACTAn important component for successful translation of cell replacement‐based therapies into clinical practice is the utilization of large animal models to conduct efficacy and/or safety cell dosing studies. Over the past few decades, several large animal models (dog, cat, nonhuman primate) were developed and employed in cell replacement studies; however, none of these models appears to provide a readily available platform to conduct effective and large‐scale preclinical studies. In recent years, numerous pig models of neurodegenerative disorders were developed using both a transgenic approach as well as invasive surgical techniques. The pig model (naïve noninjured animals) was recently used successfully to define the safety and optimal dosing of human spinal stem cells after grafting into the central nervous system (CNS) in immunosuppressed animals. The data from these studies were used in the design of a human clinical protocol used in amyotrophic lateral sclerosis (ALS) patients in a Phase I clinical trial. In addition, a highly inbred (complete major histocompatibility complex [MHC] match) strain of miniature pigs is available which permits the design of comparable MHC combinations between the donor cells and the graft recipient as used in human patients. Jointly, these studies show that the pig model can represent an effective large animal model to be used in preclinical cell replacement modeling. This review summarizes the available pig models of neurodegenerative disorders and the use of some of these models in cell replacement studies. The challenges and potential future directions in more effective use of the pig neurodegenerative models are also discussed. J. Comp. Neurol. 522:2784–2801, 2014. © 2014 Wiley Periodicals, Inc.

The authors have analyzed the religious figures Abraham, Moses, Jesus, and St. Paul from a behavioral, neurologic, and neuropsychiatric perspective to determine whether new insights can be achieved about the nature of their revelations. Analysis reveals that these individuals had experiences that resemble those now defined as psychotic symptoms, suggesting that their experiences may have been manifestations of primary or mood disorder-associated psychotic disorders. The rationale for this proposal is discussed in each case with a differential diagnosis. Limitations inherent to a retrospective diagnostic examination are assessed. Social models of psychopathology and group dynamics are proposed as explanations for how followers were attracted and new belief systems emerged and were perpetuated. The authors suggest a new DSM diagnostic subcategory as a way to distinguish this type of psychiatric presentation. These findings support the possibility that persons with primary and mood disorder-associated psychotic symptoms have had a monumental influence on the shaping of Western civilization. It is hoped that these findings will translate into increased compassion and understanding for persons living with mental illness.

Models employing peripheral nerve to bypass spinal cord injury (SCI), although highly promising, may benefit from improved nerve regeneration and motor bridge connectivity. Recent studies have demonstrated that neuronal growth factor-induced enhancement of endogenous neurorestoration may improve neuronal connectivity after severe neurologic injury, particularly if delivered intraparenchymally with zero-order kinetics. We sought to investigate the effect of convection-enhanced delivery of brain-derived neurotrophic factor (BDNF), a neuronal growth factor, on the connectivity of a peripheral motor-nerve bridge in a rodent model using electrophysiology and immunohistochemistry (IHC). Spinal cords of 29 female rats were hemisected at the L1 level. Ipsilateral T13 peripheral nerves were dissected from their muscular targets distally, while maintaining their connections with the spinal cord, and inserted caudal to the injury site to establish the nerve bridge. A microcannula attached to a six-week mini-osmotic pump was used to deliver either BDNF (n=12), saline (n=14), or fluorescein dye (n=3) directly into the spinal cord parenchyma between the site of nerve insertion and hemisection to a depth of 2mm into the area of the lateral motor pool. After four weeks, gastrocnemius muscle activation was assessed electromyographically in five animals from each group. Spinal cords were harvested and analyzed with IHC for cannula-associated injury, and nerve regeneration. Strength of motor bridge connection was illustrated by electrophysiology data. Intraspinal BDNF levels were measured using enzyme-linked immunosorbent assay. IHC revealed increased intraparenchymal BDNF concentration at the nerve bridge insertion site with evidence of minimal trauma from cannulation. BDNF infusion resulted in stronger connections between bridge nerves and spinal motor axons. Bridge nerve electrical stimulation in BDNF-treated rats evoked hind leg electromyogram responses of shorter latency and larger amplitudes than saline-infused controls. Thus, direct convection-assisted delivery provides reliable administration of potent growth factors directly into the spinal cord parenchyma. Delivery of BDNF at the peripheral nerve bridge site results in enhanced connectivity of the peripheral motor bridge in a rodent model of SCI.

Experimental protocols used for chronic infusion of neuroactive agents within regions of the brain often utilize a mini-osmotic pump system. Agents are commonly delivered via a stainless steel cannula with a diameter of 0.30mm or greater. Systems utilizing a cannula of this caliber may impose trauma to the area of interest resulting in architectural damage, thereby compromising structural integrity and normal functioning. As neuroscience inquiry becomes more sophisticated, investigation of brain structures and circuitry requires improved levels of accuracy and higher resolution. We have developed a method for the preparation and implantation of a chronic infusion system within the brain utilizing a borosilicate microcannula with a tip diameter of 50μm. This technique reduces damage to the local environment and diminishes reactive gliosis at the site of infusion. The configuration of the microinfusion system is also able to conform to the surface of the animal's skull, precluding the need for large cranial pedestals, and thus facilitating closure of the scalp incision and reducing the risk of infection. We demonstrate reliable sustained delivery of a dye having a representative molecular weight using an in vitro model and in vivo studies in rats.