Response patterns for individuals receiving contingent skin shock aversion intervention to treat violent self-injurious and assaultive behaviours.

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.

Impetuous suicidality with zolpidem use: a case report and minireview.

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.

Altered corticolimbic connectivity reveals sex-specific adolescent outcomes in a rat model of early life adversity.

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.

Having a traumatic childhood increases the risk a person will develop anxiety disorders later in life. Early life adversity affects men and women differently, but scientists do not yet know why. Learning more could help scientists develop better ways to prevent or treat anxiety disorders in men and women who experienced childhood trauma. Anxiety occurs when threat-detecting brain circuits turn on. These circuits begin working in infancy, and during childhood and adolescence, experiences shape the brain to hone the body's responses to perceived threats. Two areas of the brain that are important hubs for anxiety-related brain circuits include the basolateral amygdala (BLA) and the prefrontal cortex (PFC). Now, Honeycutt et al. show that rats that experience early life adversity develop stronger connections between the BLA and PFC, and these changes occur earlier in female rats. In the experiments, one group of rats was repeatedly separated from their mothers and littermates (an early life trauma), while a second group was not. Honeycutt et al. examined the connections between the BLA and PFC in the two groups at three different time periods during their development: the juvenile stage, early adolescence, and late adolescence. The experiments showed stronger connections between the BLA and PFC begin to appear earlier in juvenile traumatized female rats. But these changes did not appear in their male counterparts until adolescence. Lastly, the rats that developed these strengthened BLA-PFC connections also behaved more anxiously later in life. This may mean that the ideal timing for interventions may be different for males and females. More work is needed to see if these results translate to humans and then to find the best times and methods to help people who experienced childhood trauma.

First Human Trial of Stem Cell Transplantation in Complex Arrays for Stroke Patients Using the Intracerebral Microinjection Instrument.

BACKGROUND: In preclinical studies, the Intracerebral Microinjection Instrument (IMI) has demonstrated the ability to deliver therapeutics within the brain in 3-dimensional arrays from a single overlying penetration while incurring minimal localized trauma. OBJECTIVE: To evaluate the safety and performance of the IMI in its first use in humans to deliver stem cells in complex configurations within brain regions affected by ischemic injury. METHODS: As part of a phase 1 study, 3 chronically hemiparetic motor stroke patients received intracerebral grafts of the therapeutic stem cell line, NSI-566, using the IMI and its supporting surgical planning software. The patients were 37 to 54 yr old, had ischemic strokes more than 1 yr prior to transplantation, and received Fugl-Meyer motor scale scores of 17-48 at screening. During a single surgical procedure, patients received several neural grafts (42 ± 3) within the peri-infarct region targeted strategically to facilitate neural repair. RESULTS: The IMI enabled multiple cellular deposits to be safely placed peripheral to stroke lesions. The procedure was well tolerated, recovery was uneventful, and there occurred no subsequent complications. The IMI performed reliably throughout the procedures without evident targeting errors. One year after transplantation, all 3 subjects displayed significant clinical improvement, and imaging analysis demonstrated occupation of infarct cavities with new tissue without tumor formation. CONCLUSION: IMI technology permits unprecedented numbers of injections to be tactically placed in 3-dimensional arrays safely and reliably in human subjects.This advanced methodology can optimize the benefits of novel therapeutics by enabling versatile 3-dimensional intracerebral targeting.

Stable Intracerebral Transplantation of Neural Stem Cells for the Treatment of Paralysis Due to Ischemic Stroke.

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 × 107 , 2.4 × 107 , or 7.2 × 107 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.

Intracerebral Delivery in Complex 3D Arrays: The Intracerebral Microinjection Instrument.

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 used 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.

Discrepancies in stereotaxic coordinate publications and improving precision using an animal-specific atlas.

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.

Epigenetic Regulation of Glutamic Acid Decarboxylase 67 in a Hippocampal Circuit.

GABAergic dysfunction in hippocampus, a key feature of schizophrenia (SZ), may contribute to cognitive impairment in this disorder. In stratum oriens (SO) of sector CA3/2 of the human hippocampus, a network of genes involved in the regulation of glutamic acid decarboxylase GAD67 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 GAD65 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 GAD67, GAD65, 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 CA3/2, followed by laser microdissection of individual transduced GABA neurons. Quantitative PCR (QPCR) analyses demonstrated that inhibition of HDAC1 and DAXX increased expression of GAD67, GAD65, 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 GAD67 regulatory pathway in the SO of CA3/2.

Administration of electroconvulsive therapy for depression associated with deep brain stimulation in a patient with post-traumatic Parkinson's Disease: a case study.

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.

Feasibility of Three-Dimensional Placement of Human Therapeutic Stem Cells Using the Intracerebral Microinjection Instrument.

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.

Optimization of pilocarpine-mediated seizure induction in immunodeficient NodScid mice.

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 100mg/kg injections of pilocarpine have been shown to be more effective than single 300-400mg/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 ± 3.5s. 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 100mg/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.

hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice.

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.

Pig models of neurodegenerative disorders: Utilization in cell replacement-based preclinical safety and efficacy studies.

An 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.

The role of psychotic disorders in religious history considered.

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.

Convection enhanced drug delivery of BDNF through a microcannula in a rodent model to strengthen connectivity of a peripheral motor nerve bridge model to bypass spinal cord injury.

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.

Mania following vagus nerve stimulation: a case report and review of the literature.

Vagus nerve stimulation (VNS) is an increasingly used therapy for patients with treatment-refractory epilepsy and depression. Hypomanic and manic symptoms are a rare but recognized adverse effect of VNS treatment. Here we describe a case in which VNS treatment in a patient with epilepsy and unipolar depression was associated with the rapid development of manic symptoms. The patient's manic symptoms resolved with temporary discontinuation of the VNS current, and the patient was eventually able to resume VNS treatment with good effect and without further manic symptoms. Mania is a rare but serious side effect of VNS; however, in this case and in the majority of reported cases of VNS-associated mania, symptoms resolve and VNS can be safely administered.

Safety and function of a new clinical intracerebral microinjection instrument for stem cells and therapeutics examined in the Göttingen minipig.

BACKGROUND: A new intracerebral microinjection instrument (IMI) allowing multiple electrophysiologically guided microvolume injections from a single proximal injection path in rats has been adapted to clinical use by coupling the IMI to an FHC microTargeting Manual Drive, designed to be used with standard stereotactic frame-based systems and FHC frameless microTargeting Platforms. METHODS: The function and safety of the device was tested by conducting bilateral electrophysiologically guided microinjections of fluorescent microspheres in the substantia nigra of 4 Göttingen minipigs. RESULTS: The device was easy to handle and enabled accurate electrophysiologically guided targeting of the substantia nigra with minimal local tissue damage. CONCLUSION: The IMI is suitable for clinical use and may prove useful for various stereotactic procedures that require high levels of precision and/or three-dimensional distribution of therapeutics within the brain.

New-onset dissociative disorder after electroconvulsive therapy.

Electroconvulsive therapy (ECT) is an exceptionally effective treatment for a number of psychiatric conditions; however, a common adverse effect is temporary cognitive impairment, especially memory loss. The dissociative disorders also involve disturbances of memory, as well as consciousness and personal identity, but are rarely iatrogenic. We report a case in which dissociative symptoms developed after ECT. A 51-year-old woman with hypothyroidism, migraine headaches, bipolar disorder, and anorexia by history was admitted for worsening depression with suicidal ideation. After a course of 7 right-sided ECT treatments, she experienced remarkable personality change, claiming that it was 1976 and behaving as though she was 30 years younger. Neuropsychological tests were normal, and her memory and former personality spontaneously returned 2 weeks later. This case illustrates that such events may be seen in patients with certain psychiatric profiles, and further studies are needed to determine the risk factors for the occurrence of dissociative episodes after ECT.

Zinc: the brain's dark horse.

Zinc is a life-sustaining trace element, serving structural, catalytic, and regulatory roles in cellular biology. It is required for normal mammalian brain development and physiology, such that deficiency or excess of zinc has been shown to contribute to alterations in behavior, abnormal central nervous system development, and neurological disease. In this light, it is not surprising that zinc ions have now been shown to play a role in the neuromodulation of synaptic transmission as well as in cortical plasticity. Zinc is stored in specific synaptic vesicles by a class of glutamatergic or "gluzinergic" neurons and is released in an activity-dependent manner. Because gluzinergic neurons are found almost exclusively in the cerebral cortex and limbic structures, zinc may be critical for normal cognitive and emotional functioning. Conversely, direct evidence shows that zinc might be a relatively potent neurotoxin. Neuronal injury secondary to in vivo zinc mobilization and release occurs in several neurological disorders such as Alzheimer's disease and amyotrophic lateral sclerosis, in addition to epilepsy and ischemia. Thus, zinc homeostasis is integral to normal central nervous system functioning, and in fact its role may be underappreciated. This article provides an overview of zinc neurobiology and reviews the experimental evidence that implicates zinc signals in the pathophysiology of neuropsychiatric diseases. A greater understanding of zinc's role in the central nervous system may therefore allow for the development of therapeutic approaches where aberrant metal homeostasis is implicated in disease pathogenesis.