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Epileptogenesis, arising from alterations in synaptic strength, shares mechanistic and phenotypic parallels with memory formation. However, direct evidence supporting the existence of seizure memory remains scarce. Leveraging a conditioned seizure memory (CSM) paradigm, we found that CSM enabled the environmental cue to trigger seizure repetitively, and activating cue-responding engram cells could generate CSM artificially. Moreover, cue exposure initiated an analogous process of memory reconsolidation driven by mammalian target of rapamycin-brain-derived neurotrophic factor signaling. Pharmacological targeting of the mammalian target of rapamycin pathway within a limited time window reduced seizures in animals and interictal epileptiform discharges in patients with refractory seizures. Our findings reveal a causal link between seizure memory engrams and seizures, which leads us to a deeper understanding of epileptogenesis and points to a promising direction for epilepsy treatment.

The hippocampus is broadly impacted by neuromodulations. However, how neuropeptides shape the function of the hippocampus and the related spatial learning and memory remains unclear. Here, we discover the crucial role of cholecystokinin (CCK) in heterosynaptic neuromodulation from the medial entorhinal cortex (MEC) to the hippocampus. Systematic knockout of the CCK gene impairs CA3-CA1 LTP and space-related performance. The MEC provides most of the CCK-positive neurons projecting to the hippocampal region, which potentiates CA3-CA1 long-term plasticity heterosynaptically in a frequency- and NMDA receptor (NMDAR)-dependent manner. Selective inhibition of MEC CCKergic neurons or downregulation of their CCK mRNA levels also impairs CA3-CA1 LTP formation and animals' performance in the water maze. This excitatory extrahippocampal projection releases CCK upon high-frequency excitation and is active during animal exploration. Our results reveal the critical role of entorhinal CCKergic projections in bridging intra- and extrahippocampal circuitry at electrophysiological and behavioral levels., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Depression is a common mood disorder characterized by a range of clinical symptoms, including prolonged low mood and diminished interest. Although many clinical and animal studies have provided significant insights into the pathophysiology of depression, current treatment strategies are not sufficient to manage this disorder. It has been suggested that connexin (Cx)-based hemichannels are candidates for depression intervention by modifying the state of neuroinflammation. In this study, we investigated the antidepressant-like effect of a recently discovered selective Cx hemichannel inhibitor, a small organic molecule called D4. We first showed that D4 reduced hemichannel activity following systemic inflammation after LPS injections. Next, we found that D4 treatment prevented LPS-induced inflammatory response and depressive-like behaviors. These behavioral effects were accompanied by reduced astrocytic activation and hemichannel activity in depressive-like mice induced by repeated low-dose LPS challenges. D4 treatment also reverses depressive-like symptoms in mice subjected to chronic restraint stress (CRS). To test whether D4 broadly affected neural activity, we measured c-Fos expression in depression-related brain regions and found a reduction in c-Fos + cells in different brain regions. D4 significantly normalized CRS-induced hypoactivation in several brain regions, including the hippocampus, entorhinal cortex, and lateral septum. Together, these results indicate that blocking Cx hemichannels using D4 can normalize neuronal activity and reduce depressive-like symptoms in mice by reducing neuroinflammation. Our work provides evidence of the antidepressant-like effect of D4 and supports glial Cx hemichannels as potential therapeutic targets for depression., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Temporal lobe epilepsy (TLE) is one of the most common types of epilepsy, yet approximately one-third of patients are refractory to current anticonvulsive drugs, which target neurons and synapses. Astrocytic and microglial dysfunction is commonly found in epileptic foci and has been shown to contribute to neuroinflammation and hyperexcitability in chronic epilepsy. Accumulating evidence points to a key role for glial hemichannels in epilepsy, but inhibiting both connexin (Cx) gap junctions and hemichannels can lead to undesirable side effects because the former coordinate physiological functions of cell assemblies. It would be a great benefit to use an orally available small molecule to block hemichannels to alleviate epileptic symptoms. Here, we explored the effect of D4, a newly developed compound that inhibits the Cx hemichannels but not Cx gap junctions using the pilocarpine mouse model of TLE. In vitro application of D4 caused a near-complete reduction in the pilocarpine-induced cell membrane permeability associated with increased Cx hemichannel activity. Moreover, preadministration of D4 in vivo effectively reduced neuroinflammation and altered synaptic inhibition, which then enhanced the animal survival rate. Posttreatment with a single dose of D4 in vivo has prolonged effects on suppressing the activation of astrocytes and microglia and rescued the changes in neuroinflammatory and synaptic gene expression induced by pilocarpine. Collectively, these results indicate that targeting Cx hemichannels by D4 is an effective and promising strategy for treating epilepsy in which neuroinflammation plays a critical role.

Depression is a debilitating mood disorder with highly heterogeneous pathogenesis. The limbic system is well-linked to depression. As an important node in the limbic system, the lateral septum (LS) can modulate multiple affective and motivational behaviors. However, the role of LS in depression remains unclear. By using c-Fos expression mapping, we first screened and showed activation of the LS in various depression-related behavioral tests, including the forced swim test (FST), tail suspension test (TST), and sucrose preference test. In the LS, more than 10% of the activated neurons were somatostatin-expressing (SST) neurons. We next developed a microendoscopic calcium imaging method in freely moving mice and revealed that LS SST neural activity increased during mobility in the TST but not open field test. We hypothesize that LS SST neuronal activity is linked to stress and depression. In two mouse models of depression, repeated lipopolysaccharide (LPS) injection and chronic restraint stress (CRS), we showed that LS neuronal activation was suppressed. To examine whether the re-activation of LS SST neurons can be therapeutically beneficial, we optogenetically activated LS SST neurons and produced antidepressant-like effects in LPS-injected mice by increasing TST motility. Moreover, chemogenetic activation of LS SST neurons increased FST struggling in the CRS-exposed mice. Together, these results provide the first evidence of a role for LS SST neurons in regulating depressive-like behaviors in mice and identify them as a potential therapeutic target for neuromodulation-based intervention in depression.

The PI3K/Akt pathway is frequently deregulated in human cancers, and multiple Akt inhibitors are currently under clinical evaluation. Based on the experience from other molecular targeted therapies, however, it is likely that acquired resistance will be developed in patients treated with Akt inhibitors. We established breast cancer models of acquired resistance by prolonged treatment of cells with allosteric or ATP-competitive Akt inhibitors. Phospho-Receptor tyrosine kinase (Phospho-RTK) arrays revealed hyper-phosphorylation of multiple RTKS, including EGFR, Her2, HFGR, EhpB3 and ROR1, in Akt-inhibitor-resistant cells. Importantly, resistance can be overcome by treatment with an EGFR inhibitor. We further showed that cancer stem cells (CSCs) are enriched in breast tumor cells that have developed resistance to Akt inhibitors. Several candidates of CSC regulators, such as ID4, are identified by RNA sequencing. Cosmic analysis indicated that sensitivity of tumor cells to Akt inhibitors can be predicted by ID4 and stem cell/epithelial-mesenchymal transition pathway targets. These findings indicate the potential of targeting the EGFR pathway and CSC program to circumvent Akt inhibitor resistance in breast cancer.

It is well known that the state of hunger can modulate hormones and hypothalamic neural circuits to drive food-seeking behavior and consumption. However, the role the sensory cortex plays in regulating foraging is much less explored. Here, we investigated whether acute fasting in mice can alter an odor-guided foraging behavior and how it can alter neurons and synapses in the (olfactory) piriform cortex (PC). Acute hunger enhances the motivation of a mouse to search for food pellets and increases food intake. The foraging behavior strongly activates the PC, as revealed by c-Fos immunostaining. The activation of PC is accompanied by an increase in excitation-inhibition ratio of synaptic density. Fasting also enhances the phosphorylation of AMP kinase, a biochemical energy regulator. Taken together, our results uncover a new regulatory brain region and implicate the PC in controlling foraging behavior.

Homeostatic synaptic plasticity, which induces compensatory modulation of synapses, plays a critical role in maintaining neuronal circuit function in response to changing activity patterns. Activity in the anterior piriform cortex (APC) is largely driven by ipsilateral neural activity from the olfactory bulb and is a suitable system for examining the effects of sensory experience on cortical circuits. Pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) can modulate excitatory and inhibitory synapses, but its role in APC is unexplored. Here we examined the role of TNF-α in adjusting synapses in the mouse APC after experience deprivation via unilateral naris occlusion. Immunofluorescent staining revealed that activity deprivation increased excitatory, and decreased inhibitory, synaptic density in wild-type mice, consistent with homeostatic regulation. Quantitative RT-PCR showed that naris occlusion increased the expression of Tnf mRNA in APC. Critically, occlusion-induced plasticity of excitatory and inhibitory synapses was completely blocked in the Tnf knockout mouse. Together, these results show that TNF-α is an important orchestrator of experience-dependent plasticity in the APC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guo and Lau.)

Signaling by neurotrophins such as the brain-derived neurotrophic factor (BDNF) is known to modulate development of interneurons, but the circuit effects of this modulation remain unclear. Here, we examined the impact of deleting TrkB, a BDNF receptor, in parvalbumin-expressing (PV) interneurons on the balance of excitation and inhibition (E-I) in cortical circuits. In the mouse olfactory cortex, TrkB deletion impairs multiple aspects of PV neuronal function including synaptic excitation, intrinsic excitability, and the innervation pattern of principal neurons. Impaired PV cell function resulted in aberrant spiking patterns in principal neurons in response to stimulation of sensory inputs. Surprisingly, dampened PV neuronal function leads to a paradoxical decrease in overall excitability in cortical circuits. Our study demonstrates that, by modulating PV circuit plasticity and development, TrkB plays a critical role in shaping the evoked pattern of activity in a cortical network., (© 2021 The Authors. Journal of Cellular Physiology published by Wiley Periodicals LLC.)

Methylmercury (MeHg) exposure has been related to amyotrophic lateral sclerosis (ALS) pathogenesis and molecular mechanisms of its neurotoxicity has been associated to an overexpression of the Restrictive Element 1 Silencing Transcription factor (REST). Herein, we evaluated the possibility that MeHg could accelerate neuronal death of the motor neuron-like NSC34 cells transiently overexpressing the human Cu 2+ /Zn 2+ superoxide dismutase 1 (SOD1) gene mutated at glycine 93 (SOD1-G93A). Indeed, SOD1-G93A cells exposed to 100 nM MeHg for 24 h showed a reduction in cell viability, as compared to cells transfected with empty vector or with unmutated SOD1 construct. Interestingly, cell survival reduction in SOD1-G93A cells was associated with an increase of REST mRNA and protein levels. Furthermore, MeHg increased the expression of the transcriptional factor Sp1 and promoted its binding to REST gene promoter sequence. Notably, Sp1 knockdown reverted MeHg-induced REST increase. Co-immunoprecipitation experiments demonstrated that Sp1 physically interacted with the epigenetic writer Lysine-Methyltransferase-2A (KMT2A). Moreover, knocking-down of KMT2A reduced MeHg-induced REST mRNA and protein increase in SOD1-G93A cells. Finally, we found that MeHg-induced REST up-regulation triggered necropoptotic cell death, monitored by RIPK1 increased protein expression. Interestingly, REST knockdown or treatment with the necroptosis inhibitor Necrostatin-1 (Nec) decelerated MeH-induced cell death in SOD1-G93A cells. Collectively, this study demonstrated that MeHg hastens necroptotic cell death in SOD1-G93A cells via Sp1/KMT2A complex, that by epigenetic mechanisms increases REST gene expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guida, Sanguigno, Mascolo, Calabrese, Serani, Molinaro, Lau, Annunziato and Formisano.)

Information represented by principal neurons in anterior piriform cortex (APC) is regulated by local, recurrent excitation and inhibition, but the circuit mechanisms remain elusive. Two types of layer 2 (L2) principal neurons, semilunar (SL), and superficial pyramidal (SP) cells, are parallel output channels, and the control of their activity gates the output of APC. Here, we examined the hypothesis that recurrent inhibition differentially regulates SL and SP cells. Patterned optogenetic stimulation revealed that the strength of recurrent inhibition is target- and layer-specific: L1 > L3 for SL cells, but L3 > L1 for SP cells. This target- and layer-specific inhibition was largely attributable to the parvalbumin (PV), but not somatostatin, interneurons. Intriguingly, olfactory experience selectively modulated the PV to SP microcircuit while maintaining the overall target and laminar specificity of inhibition. Together, these results indicate the importance of target-specific inhibitory wiring for odor processing, implicating these mechanisms in gating the output of piriform cortex., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Synaptic deficit-induced excitation and inhibition (E/I) imbalance have been implicated in the pathogenesis of schizophrenia. Using in vivo two-photon microscopy, we examined the dynamic plasticity of dendritic spines of pyramidal neurons (PNs) and "en passant" axonal bouton of parvalbumin-expressing interneurons (PVINs) in the frontal association (FrA) cortex in two adolescent mouse models with schizophrenia-like behaviors. Simultaneous imaging of PN dendritic spines and PV axonal boutons showed that repeated exposure to N-methyl-D-aspartate receptor (NMDAR) antagonist MK801 during adolescence disrupted the normal developmental balance of excitatory and inhibitory synaptic structures. This MK801-induced structural E/I imbalance significantly correlated with animal recognition memory deficits and could be ameliorated by environmental enrichment (EE). In addition, selective chemogenetic activation of PVINs in the FrA mimicked the effects of EE on both synaptic plasticity and animal behavior, while selective inhibition of PVIN abolished EE's beneficial effects. Electrophysiological recordings showed that chronic MK801 treatment significantly suppressed the frequency of mEPSC/mIPSC ratio of layer (L) 2/3 PNs and significantly reduced the resting membrane potential of PVINs, the latter was rescued by selective activation of PVINs. Such manipulations of PVINs also showed similar effects in PV-Cre; ErbB4 fl/fl animal model with schizophrenia-like behaviors. EE or selective activation of PVINs in the FrA restored behavioral deficits and structural E/I imbalance in adolescent PV-Cre; ErbB4 fl/fl mice, while selective inhibition of PVINs abolished EE's beneficial effects. Our findings suggest that the PVIN activity in the FrA plays a crucial role in regulating excitatory and inhibitory synaptic structural dynamics and animal behaviors, which may provide a potential therapeutic target for schizophrenia treatment., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)

Background: Acute and adverse effects of ketamine on cognitive functioning have been documented. No longitudinal study has examined whether cognitive deficits can be reversed following ketamine abstinence although it has been suggested in some cross-sectional studies. This study aimed to investigate the changes in cognitive functioning among ketamine users following a 12-week abstinence from ketamine., Methods: In this longitudinal study, 114 ketamine users completed clinical and cognitive assessments at both baseline and 12-week follow-up with the following instruments: Severity of Dependence Scale, Beck Depression Inventory (BDI), Anxiety Subscale of the Hospital Anxiety Depression Scale (HADSA), and a cognitive battery., Results: BDI (p < 0.001) and HADSA (p = 0.044) scores were significantly reduced at the 12-week follow-up. Significant improvements were found in Wechsler Adult Intelligence Scale (Third edition) immediate recall (p < 0.001) and delayed recall (p < 0.001) on the Rey-Osterrieth Complex Figure Test, and in delayed recall (p < 0.001), and immediate recall (p = 0.001) on the Logical Memory component of the Wechsler Memory Scale (Third Edition) at the 12-week follow-up. Participants completed the Stroop Inference Test significantly faster (p < 0.001); and required fewer number of attempts (p < 0.001) and produced fewer perseverative errors (p < 0.001) on the Wisconsin Card Sorting Test at the 12-week follow-up., Conclusion: Chronic ketamine users' verbal and visual memory and executive functions improved after 12 weeks of ketamine abstinence., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background Behavioral dysexecutive syndrome (BDES) is a common phenomenon following stroke. To date, research has focused mainly on individual behavioral symptoms rather than a more comprehensive characterization of goal-directed behavior in stroke survivors. This cross-sectional study evaluated the prevalence and clinical correlates of BDES in Hong Kong stroke survivors. Methods and Results A total of 369 stroke survivors were recruited from a regional hospital at 3 months after their index stroke. Patients' demographic and clinical characteristics were extracted from a comprehensive stroke database. BDES was measured with the Chinese version of the Dysexecutive Questionnaire. Four neurocognitive batteries assessed domains of cognitive executive functions. The prevalence of BDES 3 months poststroke was 18.7%. At that time point, the Hospital Anxiety Depression Scale and Mini-Mental State Examination scores and the presence of depression were significant predictors of BDES in a multivariate logistic regression analysis. These parameters remained significant predictors of the Dysexecutive Questionnaire score in a linear stepwise regression analysis and together accounted for 28.5% of the variance. Current depression was predictive of the Dysexecutive Questionnaire score in patients with BDES, with a variance of 9.7%. Furthermore, compared with the non-BDES group, patients with BDES exhibited poor performance-based executive function in the Chinese version of the Frontal Assessment Battery and color trails, arrow, and category fluency tests. Conclusions Symptoms of anxiety, current depression, and global cognitive function may be independent predictors of the presence and severity of BDES 3 months poststroke. Stroke survivors with BDES exhibit poor executive functioning, including goal maintenance and semantic memory.

Chronic tinnitus, the perception of lifelong constant ringing in ear, is one capital cause of disability in modern society. It is often present with various comorbid factors that severely affect quality of life, including insomnia, deficits in attention, anxiety, and depression. Currently, there are limited therapeutic treatments for alleviation of tinnitus. Tinnitus can involve a shift in neuronal excitation/inhibition (E/I) balance, which is largely modulated by ion channels and receptors. Thus, ongoing research is geared toward pharmaceutical approaches that modulate the function of ion channels and receptors. Here, we propose a seesaw model that delineates how tinnitus-related ion channels and receptors are involved in homeostatic E/I balance of neurons. This review provides a thorough account of our current mechanistic understanding of tinnitus and insight into future direction of drug development.

The broadly-distributed, non-topographic projections to and from the olfactory cortex may suggest a flat, non-hierarchical organization in odor information processing. Layer 2 principal neurons in the anterior piriform cortex (APC) can be divided into 2 subtypes: semilunar (SL) and superficial pyramidal (SP) cells. Although it is known that SL and SP cells receive differential inputs from the olfactory bulb (OB), little is known about their projections to other olfactory regions. Here, we examined axonal projections of SL and SP cells using a combination of mouse genetics and retrograde labeling. Retrograde tracing from the OB or posterior piriform cortex (PPC) showed that the APC projects to these brain regions mainly through layer 2b cells, and dual-labeling revealed many cells extending collaterals to both target regions. Furthermore, a transgenic mouse line specifically labeling SL cells showed that they send profuse axonal projections to olfactory cortical areas, but not to the OB. These findings support a model in which information flow from SL to SP cells and back to the OB is mediated by a hierarchical feedback circuit, whereas both SL and SP cells broadcast information to higher olfactory areas in a parallel manner.

Objective: To examine the relation between neuroticism and fatigue in Chinese patients with stroke., Design: Cross-sectional study., Setting: Acute stroke unit., Participants: Survivors of ischemic stroke (N=191) recruited from the acute stroke unit between May 1, 2010, and September 1, 2011., Interventions: Not applicable., Main Outcome Measures: The personality trait of neuroticism was measured with the neuroticism subscale of the Chinese version of the NEO Five-Factor Inventory. The level of fatigue was measured with the Fatigue Assessment Scale. The National Institutes of Health Stroke Scale, Geriatric Depression Scale, Barthel Index, and Mini-Mental State Examination were administered to obtain demographic and clinical information., Results: Fatigue severity 3 months after stroke positively correlated with Geriatric Depression Scale and NEO Five-Factor Inventory neuroticism scores and negatively correlated with the Barthel Index score., Conclusions: Neuroticism, independent of depressive symptoms, is a predictor of fatigue severity 3 months after stroke. Interventions such as psychological screening programs are warranted for early detection of patients at high risk of poststroke depression., (Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Aggression and agitation are common after a stroke. The association between agitation/aggression following stroke and Health-Related Quality of Life (HRQoL) in stroke survivors is unknown. This study aimed to examine the association between agitation/aggression and HRQoL in Chinese stroke survivors., Methods: Three hundred and twenty-four stroke patients entered this cross-sectional study. Agitation/aggression was assessed using the Chinese version of Neuropsychiatric Inventory (CNPI). HRQoL was measured with the Stroke Specific Quality of Life (SSQoL)., Results: Three months after the index stroke, agitation/aggression was found in 60 (18.5%) patients. In the agitation/aggression group, 44 patients (73.3%) showed passive agitation/aggression, whereas 16 (26.7%) displayed passive and active agitation/aggression. No patients showed only active agitation/aggression. Patients with agitation/aggression were more likely to have history of diabetes and greater severity of depression, as well as lower SSQoL total score and Personality Changes and Social Role scores. Controlling for diabetes and depression severity did not alter the above results. The Energy and Thinking scores of the SSQoL were significantly lower in the passive/active agitation/aggression group relative to the passive agitation/aggression group (adjusted for CNPI aggression/agitation score)., Conclusion: In this study sample, agitation/aggression was preponderantly of the passive type and was associated with poorer HRQoL independently from depression or medical conditions. Patients with both passive and active agitation/aggression had lower Quality of Life (QoL) than patients with only passive agitation/aggression. The causality of the association between low QoL and agitation/aggression needs to be explored in future studies.

In utero exposure to certain chemicals can impair embryo development, causing embryonic death, growth retardation, or severe birth defects. Establishment of effective in vitro tests is crucial for identifying developmental toxicants and for reducing the financial and ethical burden of animal-based tests. Previously, we created an in vitro morphogenesis model using pluripotent P19C5 mouse embryonal carcinoma stem cells that mimics the process of gastrulation and axial body elongation of embryos. Because many birth defects are caused by dysregulation of cellular behaviors during embryogenesis, the morphogenesis model may serve as a unique tool to investigate the impacts of developmental toxicants. The aim of this study is to evaluate the applicability and limitations of the model using 20 therapeutic drugs, 16 of which are contraindicated in pregnancy and 4 are considered safe. P19C5 embryoid bodies (EBs) were exposed to different concentrations of drugs during 4 days of 3-dimensional culture. The treatment effects on growth and morphogenesis were analyzed using morphometric measurements of EB size and shape, respectively. Viability assays of P19C5 cells and NIH/3T3 fibroblasts were used to determine the drug concentrations that caused general cytotoxicity and those that selectively diminished P19C5 proliferation relative to NIH/3T3 proliferation. Thirteen contraindicated drugs diminished P19C5 cell proliferation, reduced EB growth, or altered morphogenesis at concentrations below generally cytotoxic levels. Two safe drugs also exhibited these impacts at the highest concentration tested. Although additional validation studies are required, this study introduces morphogenesis-based stem cell models as potentially effective in vitro tools for developmental toxicity research., (© The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Pain is common in stroke; however, its impacts on health-related quality of life (HRQoL) are unclear due to the limitations of previous studies., Objectives: The current study aims to examine and compare the demographic and clinical characteristics of Chinese stroke patients with and without pain and explore the correlations between poststroke pain and HRQoL., Method: Four hundreds and forty-one participants recruited in an acute stroke unit in a regional hospital. They were assessed 3 months after the index stroke with the following instruments. HRQoL was measured using the Short Form-12 (SF-12). The Chinese version of the Faces Pain Rating Scale-Revised (FPS-R) was used to determine the presence and intensity of pain. The demographic and clinical characteristics of patients were obtained using Barthel Index (BI), Fatigue Severity Scale (FSS), Geriatric Depression Scale (GDS), Anxiety subscale of the Hospital Anxiety and Depression Scale (HADSA), Instrumental Activities of Daily Living (IADL), Mini Mental State Examination (MMSE), Modified Rankin Scale (MRS), and National Institutes of Health Stroke Scale (NIHSS)., Results: Of all participants screened, 167 reported pain and 69 had novel pain. The pain group had significantly lower physical component summary (PCS) scores after adjusting for sex, education, DSM-IV depression and BI, GDS, HADSA, and FSS scores. The FPS score was negatively correlated with a lower PCS score in patients with pain and with novel pain., Conclusion: The presence and intensity of pain have significant negative effects on HRQoL in stroke survivors. Interventions for pain could make a valuable contribution to improving HRQoL in stroke survivors.

Background: Both apathy and suicide are common in poststroke patients. However, the association between poststroke apathy and suicide-related ideation (SI) in Chinese stroke patients is not clear and poorly understood. The aim of this study was to examine the association between apathy and SI in stroke., Methods: A cross-sectional study was conducted to investigate the association in 518 stroke survivors from Acute Stroke Unit of the Prince of Wales Hospital in Hong Kong. Geriatric Mental State Examination-Version A (GMS) and Neuropsychiatric Inventory-apathy subscale (NPI-apathy) were employed to assess poststroke SI and apathy, respectively. Patients' clinical characteristics were obtained with the following scales: the National Institutes of Health Stroke Scale (NIHSS), the Mini-Mental State Examination (MMSE), and the Geriatric Depression Scale (GDS)., Results: Thirty-two (6.2%) stroke survivors reported SI. The SI group had a significantly higher frequency of NPI-apathy than the non-SI group (31.2% vs 5.3%, p < 0.001). The SI group also had higher GDS scores (10.47 ± 3.17 vs 4.24 ± 3.71, p < 0.001). Regression analysis revealed that NPI-apathy (OR 2.955, 95% CI 1.142-7.647, p = 0.025) was a significant predictor of SI. The GDS score also predicted SI (OR 1.436, 95% CI 1.284-1.606, p < 0.001)., Conclusions: The current findings show that poststroke apathy is an independent predictor of SI 3 months after stroke. Early screening for and intervention targeting apathy through medication and psychological treatments may be necessary to improve stroke patients' apathy and reduce SI.

Various compounds, including therapeutic drugs, can adversely impact the survival and development of embryos in the uterus. Identification of such development-interfering agents is a challenging task, although multi-angle approaches--including the use of in vitro toxicology studies involving embryonic stem cells--should alleviate some of the current difficulties. In the present study, we utilized the in vitro elongation of embryoid bodies (EBs) derived from mouse embryonal carcinoma stem cell line P19C5 as a model of early embryological events, specifically that of gastrulation and axial patterning. From our study, we identified donepezil, a medication indicated for the management of Alzheimer's disease, as a potential developmental toxicant. The extent of P19C5 EB axial elongation was diminished by donepezil in a dose-dependent manner. Although donepezil is a known inhibitor of acetylcholinesterase, interference of elongation was not mediated through this enzyme. Quantitative reverse-transcriptase PCR revealed that donepezil altered the expression pattern of a specific set of developmental regulator genes involved in patterning along the anterior-posterior body axis. When tested in mouse whole embryo culture, donepezil caused morphological abnormalities including impaired somitogenesis. Donepezil also diminished elongation morphogenesis of EBs generated from human embryonic stem cells. These results suggest that donepezil interferes with axial elongation morphogenesis of early embryos by altering the expression pattern of regulators of axial development., (© 2014 Wiley Periodicals, Inc.)

Objective: To examine differences in health-related quality of life (HRQOL) in stroke survivors with and without apathy., Design: Cross-sectional study., Setting: Acute stroke unit in a regional hospital., Participants: Stroke survivors (N=391) recruited from the acute stroke unit., Interventions: Not applicable., Main Outcome Measures: Participants were divided into apathy and nonapathy groups. Participants who scored ≥36 on the Apathy Evaluation Scale, clinician's version formed the apathy group. HRQOL was measured with the 2 component scores, mental component summary (MCS) and physical component summary (PCS), of the Medical Outcomes Study 12-Item Short-Form Health Survey (SF-12). Demographic and clinical information were obtained with the National Institutes of Health Stroke Scale (NIHSS), Barthel Index (BI), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS)., Results: Thirty-six (9%) participants had apathy. The apathy group had significantly lower MCS and PCS scores. After adjusting for sex, education, diabetes mellitus, and NIHSS, MMSE, GDS, and BI scores, the MCS score in the apathy group remained significantly lower., Conclusions: Apathy has a significant negative effect on HRQOL in stroke survivors, particularly on their mental health. Interventions for apathy could improve the HRQOL of stroke survivors., (Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

One hundred primary ketamine users and 100 controls were recruited in Hong Kong between December 2009 and December 2011. Cognitive assessment included general intelligence, working, verbal, and visual memory, and executive functions. A Univariate General Linear Model was used to compare cognitive performance between the male and female ketamine users and controls. The female users appeared to have a higher risk of visual memory impairment than their male counterparts. Further studies are warranted to clarify the mechanism of the sex-specific effect of ketamine on cognitive functions.

The NMDA-type glutamate receptor (NMDAR) is essential for synaptogenesis, synaptic plasticity, and higher cognitive function. Emerging evidence indicates that NMDAR Ca(2+) permeability is under the control of cAMP/protein kinase A (PKA) signaling. Whereas the functional impact of PKA on NMDAR-dependent Ca(2+) signaling is well established, the molecular target remains unknown. Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca(2+) permeation and Ca(2+) signaling in spines. Activation of β-adrenergic and D1/D5-dopamine receptors induces Ser1166 phosphorylation. Loss of this single phosphorylation site abolishes PKA-dependent potentiation of NMDAR Ca(2+) permeation, synaptic currents, and Ca(2+) rises in dendritic spines. We further show that adverse experience in the form of forced swim, but not exposure to fox urine, elicits striking phosphorylation of Ser1166 in vivo, indicating differential impact of different forms of stress. Our data identify a novel molecular and functional target of PKA essential to NMDAR-mediated Ca(2+) signaling at synapses and regulated by the emotional response to stress.

Objective: To examine the impact of anxiety on health-related quality of life (HRQOL) of stroke survivors., Design: Cross-sectional study., Setting: Acute stroke unit in a regional hospital., Participants: Patients (N=374) from an acute stroke unit., Interventions: Not applicable., Main Outcome Measures: The presence of anxiety was defined as a score of ≥8 on the anxiety subscale of the Hospital Anxiety Depression Scale. HRQOL was measured by the total score and 12 domain scores of the Stroke Specific Quality of Life (SSQOL) scale. Demographic characteristics and history of medical conditions were also recorded. Clinical characteristics were obtained using the following scales: National Institutes of Health Stroke Scale, Barthel Index, Mini-Mental State Examination, and Geriatric Depression Scale (GDS)., Results: Eighty-six (23%) stroke survivors had anxiety. The anxiety group had significantly more women (62.8% vs 35.1%), higher GDS scores (7.5±4.5 vs 3.5±3.6), and lower scores for total SSQOL (3.9±0.6 vs 4.5±0.6) and SSQOL domains of energy (2.0±1.2 vs 3.4±1.4), mood (3.6±1.5 vs 4.6±0.9), personality (3.4±1.7 vs 4.4±1.1), and thinking (2.4±1.2 vs 3.5±1.4), after adjustment for sex and GDS score. In subsequent multivariate regression analysis, the Hospital Anxiety Depression Scale anxiety score was negatively associated with the SSQOL total score (r=-.154) and 5 of the 12 domain scores, namely energy (r=-.29), mood (r=-.102), personality (r=-.195), thinking (r=-.136), and work/productivity (r=-.096)., Conclusions: Anxiety has a negative effect on HRQOL of stroke survivors, independent from depression. Interventions for anxiety should improve stroke survivors' quality of life., (Copyright © 2013 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Rationale: Cognitive impairment has been found to be reversible in people with substance abuse, particularly those using ketamine. Ketamine users are often poly-substance users. This study compared the cognitive functions of current and former ketamine users who were also abusing other psychoactive substances with those of non-users of illicit drugs as controls., Methods: One hundred ketamine poly-drug users and 100 controls were recruited. Drug users were divided into current (n = 32) and ex-users (n = 64) according to the duration of abstinence from ketamine (>30 days). The Beck Depression Inventory (BDI), the Hospital Anxiety Depression Scale (HADSA) and the Severity of Dependence Scale (SDS) were used to evaluate depression and anxiety symptoms and the severity of drug use, respectively. The cognitive test battery comprised verbal memory (Wechsler Memory Scale III: Logic Memory and Word List), visual memory (Rey-Osterrieth Complex Figure, ROCF), executive function (Stroop, Wisconsin Card Sorting Test, and Modified Verbal Fluency Test), working memory (Digit Span Backward), and general intelligence (Information, Arithmetic and Digit-Symbol Coding) tests., Results: Current users had higher BDI and HADSA scores than ex-users (p < 0.001 for BDI and p = 0.022 for HADSA) and controls (p < 0.001 for BDI and p = 0.002 for HADSA). Ex-users had higher BDI (p = 0.006) but equal HADSA scores (p = 1.000) compared to controls. Both current and ex-users had lower scores on Logical Memory delayed recall (p = 0.038 for current users and p = 0.032 for ex-users) and ROCF delayed recall (p = 0.033 for current users and p = 0.014 for ex-users) than controls. Current users also performed worse on ROCF recognition than controls (p = 0.002). No difference was found between the cognitive functions of current and ex-users., Conclusions: Ketamine poly-drug users displayed predominantly verbal and visual memory impairments, which persisted in ex-users. The interactive effect of ketamine and poly-drug use on memory needs further investigation., (© 2013 Elsevier Ltd. All rights reserved.)

Objective: Both cognitive impairment and depressive symptoms have been reported in ketamine users. However, no previous study has examined the relationship between them. This study aimed to examine cognitive functions and depressive symptoms and their relationship in young ketamine users in Hong Kong., Method: Fifty-one current ketamine users, 49 ex-ketamine users, and 100 healthy controls were recruited from counseling and youth centers in Hong Kong in this cross-sectional study. Cognitive assessment included mental and motor speed; working, verbal, and visual memory; and executive functions. Depressive symptoms were measured using the Beck Depression Inventory. One-way analyses of covariance (ANCOVA) and chi-square tests were used to analyze participants' demographic data, patterns of drug use, Beck Depression Inventory score, and performance in a cognitive battery. Cognitive functions were adjusted for age, gender, and education using ANCOVA. Correlations between the Beck Depression Inventory score and cognitive functions were examined using Pearson's correlation coefficient., Results: Cognitive impairment was found only in current ketamine users in the domains of mental and motor speed (p < .001), visual and verbal memory (p < .001), and executive functions (p < .001). Depressive symptoms were also more frequently found in current ketamine users (p < .001). Correlations between depressive symptoms and certain cognitive scores were statistically significant but modest., Conclusions: Current ketamine use is associated with cognitive impairment. Illicit substance treatment and rehabilitation services should pay attention to ketamine's cognitive effects and motivate their clients to quit using ketamine and stay abstinent.

Persistent alterations in network activity trigger compensatory changes in excitation and inhibition that restore neuronal firing rate to an optimal range. One example of such synaptic homeostasis is the downregulation of inhibitory transmission by chronic inactivity, in part through the reduction of vesicular transmitter content. The enzyme glutamic acid decarboxylase 67 (GAD67) is critical for GABA synthesis, but its involvement in homeostatic plasticity is unclear. We explored the role of GAD67 in activity-dependent synaptic plasticity using a mouse line (Gad1(-/-)) in which GAD67 expression is disrupted by genomic insertion of the green fluorescent protein (GFP). Homozygous deletion of Gad1 significantly reduced miniature inhibitory postsynaptic current (mIPSC) amplitudes and GABA levels in cultured hippocampal neurons. The fractional block of mIPSC amplitude by a low affinity, competitive GABA(A) receptor antagonist was higher in GAD67-lacking neurons, suggesting that GABA concentration in the synaptic cleft is lower in knockout animals. Chronic suppression of activity by the application of tetrodotoxin (TTX) reduced mIPSC amplitudes and the levels of GAD67 and GABA. Moreover, TTX reduced GFP levels in interneurons, suggesting that GAD67 gene expression is a key regulatory target of activity. These in vitro experiments were corroborated by in vivo studies in which olfactory deprivation reduced mIPSC amplitudes and GFP levels in glomerular neurons in the olfactory bulb. Importantly, TTX-induced downregulation of mIPSC was attenuated in Gad1(-/-) neurons. Altogether, these findings indicate that activity-driven expression of GAD67 critically controls GABA synthesis and, thus, vesicular filling of the transmitter.

The aim of this cross-sectional study was to determine the socio-demographic and clinical factors associated with depressive symptoms in the family caregivers of Hong Kong Chinese stroke patients. One hundred and twenty-three patients at a stroke clinic and their family caregivers formed the study sample. The depressive symptoms of both the patients and their family caregivers were rated with the Chinese version of the 15-item Geriatric Depression Scale (GDS). Participants' socio-demographic data and clinical characteristics served as the independent variables in relation to the caregivers' GDS scores. Patients' and caregivers' somatic and psychological conditions were measured with 10 scales. In univariate analysis, caregivers' GDS scores were significantly correlated with certain of their characteristics [Modified Life Event Scale (MLES), Cumulative Illness Rating Scale (CIRS) and Lubben Social Network Scale (LSNS) scores, sex and being a housewife] and those of the patients (GDS score and being a housewife). Multiple regression analysis showed caregivers' MLES and CIRS scores and patients' GDS scores to be independent correlates of caregivers' GDS scores. Adverse events encountered by caregivers in the past 6 months, their current health problems and patients' depressive symptoms were found to be the principal factors associated with caregivers' depressive symptoms., (© 2011 Blackwell Publishing.)

Objective: To ascertain the clinical and sociodemographic factors associated with family caregivers' burden in Chinese patients with stroke in Hong Kong., Design: Cross-sectional design., Setting: Stroke Clinic., Participants: Patients (N=123) from a stroke clinic and their family caregivers., Interventions: Not applicable., Main Outcome Measures: Predictive factors of family caregivers' burden in Chinese stroke patients in Hong Kong. Caregivers' burden was assessed with the Caregiving Burden Scale (CBS). Patients' and caregivers' sociodemographic data and clinical characteristics were recorded. Physical and psychological conditions were measured and rated with the following instruments: Cumulative Illness Rating Scale, Geriatric Depression Scale (GDS), Barthel Index, Instrumental Activities of Daily Living, Mini-Mental State Examination, Lubben Social Network Scale, Modified Life Event Scale (MLES), Hospital Anxiety and Depression Scale (HADS), and a single question about fatigue., Results: In the univariate analysis, the CBS score had significant correlations with certain characteristics of caregivers (sex, GDS, HADS, depressive symptoms, fatigue, and MLES) and those of patients' (sex, age, education, GDS). Regression analysis revealed that caregivers' GDS and patients' education were the independent correlates of the CBS., Conclusions: The severity of depressive symptoms in Chinese stroke caregivers and patients' education are independent factors associated with the caregivers' burden. Further studies evaluating interventions on caregivers' burden should include the assessment and management of mood disorders., (Copyright © 2011 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Protein kinase C (PKC) enhances NMDA receptor (NMDAR)-mediated currents and promotes NMDAR delivery to the cell surface via SNARE-dependent exocytosis. Although the mechanisms of PKC potentiation are established, the molecular target of PKC is unclear. Here we show that synaptosomal-associated protein of 25 kDa (SNAP-25), a SNARE protein, is functionally relevant to PKC-dependent NMDAR insertion, and identify serine residue-187 as the molecular target of PKC phosphorylation. Constitutively active PKC delivered via the patch pipette potentiated NMDA (but not AMPA) whole-cell currents in hippocampal neurons. Expression of RNAi targeting SNAP-25 or mutant SNAP-25(S187A) and/or acute disruption of the SNARE complex by treatment with BoNT A, BoNT B or SNAP-25 C-terminal blocking peptide abolished NMDAR potentiation. A SNAP-25 peptide and function-blocking antibody suppressed PKC potentiation of NMDA EPSCs at mossy fiber-CA3 synapses. These findings identify SNAP-25 as the target of PKC phosphorylation critical to PKC-dependent incorporation of synaptic NMDARs and document a postsynaptic action of this major SNARE protein relevant to synaptic plasticity.

NMDARs (N-methyl-D-aspartate receptors) are critical for synaptic function throughout the CNS (central nervous system). NMDAR-mediated Ca(2+) influx is implicated in neuronal differentiation, neuronal migration, synaptogenesis, structural remodelling, long-lasting forms of synaptic plasticity and higher cognitive functions. NMDAR-mediated Ca(2+) signalling in dendritic spines is not static, but can be remodelled in a cell- and synapse-specific manner by NMDAR subunit composition, protein kinases and neuronal activity during development and in response to sensory experience. Recent evidence indicates that Ca(2+) permeability of neuronal NMDARs, NMDAR-mediated Ca(2+) signalling in spines and induction of NMDAR-dependent LTP (long-term potentiation) at hippocampal Schaffer collateral-CA1 synapses are under control of the cAMP/PKA (protein kinase A) signalling cascade. Thus, by enhancing Ca(2+) influx through NMDARs in spines, PKA can regulate the induction of LTP. An emerging concept is that activity-dependent regulation of NMDAR-mediated Ca(2+) signalling by PKA and by extracellular signals that modulate cAMP or protein phosphatases at synaptic sites provides a dynamic and potentially powerful mechanism for bi-directional regulation of synaptic efficacy and remodelling.

The number and subunit composition of synaptic N-methyl-D-aspartate receptors (NMDARs) are not static, but change in a cell- and synapse-specific manner during development and in response to neuronal activity and sensory experience. Neuronal activity drives not only NMDAR synaptic targeting and incorporation, but also receptor retrieval, differential sorting into the endosomal-lysosomal pathway and lateral diffusion between synaptic and extrasynaptic sites. An emerging concept is that activity-dependent, bidirectional regulation of NMDAR trafficking provides a dynamic and potentially powerful mechanism for the regulation of synaptic efficacy and remodelling, which, if dysregulated, can contribute to neuropsychiatric disorders such as cocaine addiction, Alzheimer's disease and schizophrenia.

Calcium (Ca2+) influx through NMDA receptors (NMDARs) is essential for synaptogenesis, experience-dependent synaptic remodeling and plasticity. The NMDAR-mediated rise in postsynaptic Ca2+ activates a network of kinases and phosphatases that promote persistent changes in synaptic strength, such as long-term potentiation (LTP). Here we show that the Ca2+ permeability of neuronal NMDARs is under the control of the cyclic AMP-protein kinase A (cAMP-PKA) signaling cascade. PKA blockers reduced the relative fractional Ca2+ influx through NMDARs as determined by reversal potential shift analysis and by a combination of electrical recording and Ca2+ influx measurements in rat hippocampal neurons in culture and hippocampal slices from mice. In slices, PKA blockers markedly inhibited NMDAR-mediated Ca2+ rises in activated dendritic spines, with no significant effect on synaptic current. Consistent with this, PKA blockers depressed the early phase of NMDAR-dependent LTP at hippocampal Schaffer collateral-CA1 (Sch-CA1) synapses. Our data link PKA-dependent synaptic plasticity to Ca2+ signaling in spines and thus provide a new mechanism whereby PKA regulates the induction of LTP.

The effect was evaluated in normal subjects of the subjective perception of motion of a small visual target (VT) when combined with the effect of vestibular stimulation produced by different magnitudes of constant angular accelerations in the dark or the effect of optokinetic stimulation produced by different constant velocities of rotation. The visual target appeared to the subject to travel more slowly and for a shorter duration when it moved in the direction of the body's angular acceleration or against that of the optokinetic drum. The perceived error in motion was: (i) in the same direction as the subject's motion sensation produced by either of the two stimuli, and (ii) quantitatively related, although differently, to the magnitude of each of the two stimulus modalities; an heuristic model is proposed to account for these observations.

The results of experiments are evaluated in terms of a simple model for the interaction of eye movement responses to simultaneous optokinetic and vestibular stimuli. The model predictions agree with the results of these experiments and explain many clinical observations concerning the effect of vision on nystagmus. The model accounts for the dominance of the visual system's response over the vestibular system's response at low frequencies. It also accounts for the inability of patients with decreased smooth pursuit system response to suppress the vestibulo-ocular reflex during simultaneous optokinetic and vestibular stimulations. The model provides useful information for the design of combined optokinetic and vestibular stimuli for test vestibulo-ocular reflexes.

Eye movement recordings in two patients with downbeat nystagmus demonstrated an unusual finding of severely impaired smooth pursuit and relatively unimpaired optokinetic nystagmus (OKN). OKN was characterized by a remarkable, slow build-up of slow-component velocity, similar to that found in afoveate animals. Optokinetic after-nystagmus (OKAN), or transient persistence of nystagmus after cessation of visual stimulation, typical of the optokinetic response of normal human subjects, was also preserved in these patients. These observations suggest that the normal contribution of smooth pursuit to the ocular motor response to rotation of the visual environment can be selectively removed by a lesion at the level of the craniocervical junction.

Measurements were made of the lesion-induced changes in vestibulo-ocular reflexes to rotatory stimuli in a group of patients with total unilateral labyrinthine paralysis and in a group with partial unilateral labyrinthine paralysis. Significant differences were found in the amplitude and phase of the response to low-frequency rotation and in the time constant of the post-rotatory response to impulsive rotation between normal subjects and patients with total unilateral labyrinthine paralysis. The results were evaluated by the use of a simplified model of vestibular function that allows the parametric evaluation of the characteristics of vestibular responses. It was found that changes in vestibulo-ocular reflex characteristics take place in parallel in both the time constant and the sensitivity of the system parameters used to describe the responses. The physiologic significance of the changes and their implication for diagnostic purposes are discussed.

1. The firing rates of action potentials of abducens nerve single fibers were recorded in the cat's orbit during a variety of vestibular and optokinetic stimulations. 2. Comparison was made of the neural firing rates associated with agonist and antagonist responses during slow and fast components of vestibular and optokinetic nystagmus. It was found that the relationship between the motoneuron firing rates and the eye motion was independent of the reflex with which they were associated--vestibular or optokinetic, or the type of response--agonist or antagonist. No neurons were observed that responded only during the fast or only during the slow nystagmus phase. Motoneuron firing rates were proportional to both velocity and position of the eye in a ratio of 1 (spikes/s)/(deg/s) to 7.2 (spikes/s)/deg. The behavior of the motoneurons was compatible with the hypothesis that thier firing rates are sufficient to overcome both elastic and viscous forces by which the muscles and ligaments hold the eye in the orbit. 3. For low-frequency head rotations, eye displacement and neural responses showed a small phase angle difference. At higher frequencies, however, while the eyes maintained a fixed relationship to the head rotation, the neural responses showed an increasing phase lead. One component of this phase lead compensated for the phase lag introduced by the orbital mechanics. The other was modeled as a constant delay of approximately 70 ms, which may be accounted for by neuromuscular transmission and transduction.

Experiments were conducted to quantify the effect of a vestibular stimulation of known magnitude on a constant optokinetic nystagmus (OKN). Ten normal human subjects were tested with varying magnitudes of vestibular stimuli that were superimposed on a constant 30 degrees optokinetic stimulus. The gain of the vestibular system in the dark was 0.42 +/- 0.11, and the gain in the light during superimposition testing was 0.12 +/- 0.02. From these results, predictions were made that the degree of vestibular imbalance necessary to produce an asymmetric OKN would generate a spontaneous nystagmus in the dark, which would be equivalent to 20 to 30 degrees. Data from a large group of patients were used for corroboration of the results.

The feasibility of replacement of the caloric test with sinusoidal rotatory stimulations of differing frequencies was investigated in ten normal subjects and seven patients with unilateral labyrinthine paralysis. Testing was performed at frequencies ranging from 0.0125 to 0.2 Hz at 60 degrees/sec and at 0.05 Hz at peak velocities of 30 degrees/sec to 180 degrees/sec. Gain, phase, and asymmetry of the nystagmic responses were measured in these groups. Results indicated that the rotatory test was not reliable enough to be used as the sole measure for identifying patients with unilateral labyrinthine lesions.

The existence of a threshold for the production of fast components of vestibular nystagmus was investigated in the rabbit. The characteristics (position and velocity) of reflexive eye movements were precisely monitored with the use of the search-coil method and a laboratory computer. The threshold largely depended on the eye position in the orbit during nystagmus and, to a much lesser extent, on the eye velocity. The basic characteristics of the threshold remained unchanged under vestibular stimulation in the dark and in the light, and for different frequencies and peak velocities of rotation. A pattern of vestibular nystagmus was demonstrated whereby it is possible to predict the occurrence of fast components.

The significance of Ewald's second law in the evaluation of the vestibulo-ocular reflex (VOR) was investigated using the transfer characteristics of the vestibular and VOR systems in normal rabbits and rabbits in which one horizontal semicircular canal had been blocked. The transfer characteristics of the vestibular system were derived from the experimental results reported by Goldberg and Fernández in 1971. A comparison was made of the properties of the bilateral and monolateral VOR systems with the predictions of a piecewise linear model of the vestibular system. The data received quantitatively collaborate the prediction of Ewald's second law as it applies to the VOR responses.

The vestibular and optokinetic ocular control systems were studied in 10 patients with cerebellar atrophy and in 10 normal subjects using (1) constant velocity optokinetic stimulation, (2) sinusoidal rotation in the dark, and (3) sinusoidal rotation in the light with a surrounding fixed optokinetic drum. The gain (maximum slow component velocity/maximum head or drum velocity) of induced nystagmus was calculated from electro-oculographic recordings. Optokinetic nystagmus was abnormal in seven patients and the average optokinetic gain in the patients was significantly (p less than 0.01) less than that of the normal group. Three patients with "clinically pure" cerebellar atrophy had increased vestibular responses, and one patient with clinical signs of peripheral neuropathy had decreased responses, probably due to associated vestibular nerve disease. The average vestibulo-ocular reflex gain in patients did not differ significantly from controls (p greater than 0.05). Three patients had normal vestibular and optokinetic responses when tested independently, but had abnormal visual-vestibular interaction. These patients probably had selective disorders of the midline cerebellar pathways that mediate visual-vestibular interaction. By studying each system, both independently and during interaction, all patients were identified as abnormal, and a more precise anatomic localization of the atrophy was obtained.

The vestibulo-ocular reflex (VOR) during rotation, optokinetic nystagmus (OKN), and interactions between the vestibulo-ocular and optokinetic systems were studied quantitatively in 10 normal human subjects, 15 patients with unilateral horizontal semicircular canal paralysis (UP), and 11 patients with bilateral horizontal semicircular canal paralysis (BP). The OKN gain (eye velocity/drum velocity) was not significantly different between the normal subjects and the patient groups. During tests in which rotatory and visual stimuli were presented simultaneously, the contribution to the observed eye movements by the VOR was only one-fourth to one-third of its gain during rotation in the dark in the normal subjects and UP patients. These interactive tests did not differentiate UP patients from normal subjects but did separate BP patients from normal subjects.