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Biomedical subjects

Richard B Rosse

Publications and source records attributed to Richard B Rosse.

At least 19 recordsLinked to original sources
PubMed2006

Imitation of facial expressions in schizophrenia.

Diminished facial expressivity is a common feature of schizophrenia that interferes with effective interpersonal communication. This study was designed to determine if real-time visual feedback improved the ability of patients with schizophrenia to imitate and produce modeled facial expressions. Twenty patients with schizophrenia and 10 controls viewed static images of facial expressions and were asked to imitate them. Half of the images were imitated with the use of a mirror and half were imitated without the use of a mirror. In addition, we examined whether practice in imitating and producing expressions improved the ability of participants to generate facial expressions on their own, without the aid of a model or mirror. Participants' facial expressions were photographed with a digital camera and each was rated for accuracy in producing characteristic facial expressions. Patients with schizophrenia were less accurate in imitating and producing facial expressions than controls, and real-time visual feedback did not improve accuracy in either group. Preliminary findings suggest that exposure to model expressions and practice in generating these expressions can improve the accuracy of certain posed expressions in schizophrenia.

Adult↗
PubMed2006

Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of alzheimer's disease, frontotemporal dementia and schizophrenia with therapeutic implications.

Two members of the family of low-density lipoprotein receptors (i.e., very low-density lipoprotein [VLDL] receptor and apolipoprotein E [apoE] type 2 receptor) are expressed in brain, where they bind and transduce reelin, a secreted glycoprotein that shares structural analogies with extracellular matrix proteins. In the developing fetal brain, reelin-signal transduction is critical for the correct positioning of neurons and the formation of appropriate synaptic connections, whereas in the mature brain, reelin participates in the mediation of experience-dependent synaptic plasticity. An important "downstream" consequence of the reelin-signal transduction cascade is inhibition of the phosphorylation of tau, a protein that regulates microtubule assembly and stability. Importantly, hyperphosphorylated tau comprises the paired helical filament, whose pathological deposition as neurofibrillary tangles is implicated in Alzheimer's disease; hyperphosphorylated tau is also implicated in the pathogenesis of other neurodegenerative disorders. Isoforms of apoE may affect the binding of reelin to its cell surface receptors and, thereby, influence tau phosphorylation, whereas insulin, insulin-like growth factor-1, and the lithium ion have actions within the cell at the level of the specific tyrosine kinases involved in the phosphorylation of tau. These data support the exploration of pharmacotherapeutic interventions designed to prevent or reduce the burden of hyperphosphorylated tau. Impaired reelin-signal transduction due to an actual deficiency of reelin expression may occur in at least some patients with psychotic disorders, especially schizophrenia; conceivably, hyperphosphorylation of tau would result from deficient transduction of reelin in schizophrenia. Schizophrenia has been conceptualized as a neurodevelopmental disorder of impaired synaptic "connectivity", whose consequence does not become fully apparent until late adolescence or early adulthood. In summary, hyperphosphorylation of tau may be an underlying point of pathological convergence for several neuropsychiatric disorders, and prevention of tau hyperphosphorylation may be an important therapeutic target.

Aging↗
PubMed2006

Modulatory effects of d-serine and sarcosine on NMDA receptor-mediated neurotransmission are apparent after stress in the genetically inbred BALB/c mouse strain.

Abnormalities of NMDA receptor-mediated neurotransmission are involved in the pathophysiology of schizophrenia, Alzheimer's disease, substance abuse and seizure disorders. The NMDA receptor is implicated in schizophrenia because phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, binds to a hydrophobic domain within the channel, precipitating a schizophreniform psychosis in susceptible persons. Pharmacological, environmental, and genetic variables alter NMDA receptor-mediated neurotransmission. Inbred mouse strains differ in their sensitivity to some of the behavioral effects of MK-801 (dizocilpine), a PCP analogue. The NMDA receptor complex in the BALB/c strain could reflect a unique stoichiometric combination of receptor subunits resulting in a higher proportion of the channels in the open configuration, a higher affinity of MK-801 for its hydrophobic channel domain, and/or a combination of the above. The BALB/c mouse strain, "stressed" mice, and behavioral consequences of MK-801 administration represent models of altered glutamatergic neural transmission. We were interested in examining the effect of stress on the modulatory properties of d-serine and sarcosine. d-Serine is a naturally occurring glycine agonist that modulates the ability of l-glutamate to influence the opening of the NMDA receptor-associated ionophore, and sarcosine is a naturally occurring glycine reuptake inhibitor. The data suggest that 24h after stress, d-serine and sarcosine interact synergistically to reduce MK-801's ability to antagonize electrically precipitated tonic hindlimb extension. Under conditions of stress, modulatory effects of d-serine and sarcosine on the antiseizure effect of MK-801 are observed that are not apparent in the nonstress condition. The results could be relevant to the development of glycinergic interventions for the treatment of neuropsychiatric disorders.

Analysis of Variance↗
PubMed2006

Exogenously administered D-serine failed to potentiate the ability of MK-801 to antagonize electrically precipitated seizures in nonhandled control and stressed mice.

NMDA receptor hypofunction (NRH) has been implicated in the pathophysiology of schizophrenia because of the ability of phencyclidine (PCP), a noncompetitive NMDA receptor antagonist, to precipitate a schizophreniform psychosis. The possible role that NRH plays in the pathophysiology of schizophrenia stimulated characterization of behaviors elicited by PCP and its analogues. For example, MK-801 (dizocilpine), a noncompetitive NMDA receptor antagonist that binds with higher affinity to the same hydrophobic channel domain as PCP, raises the threshold voltage required for the electrical precipitation of tonic hindlimb extension in mice. This ability of MK-801 is significantly reduced following stress. We showed that an exogenously administered glycine prodrug (i.e., milacemide) was able to potentiate MK-801's antiseizure efficacy in unstressed mice and restore MK-801's antiseizure efficacy in stressed animals. d-Serine may serve as an endogenous agonist for the obligatory glycine co-agonist site on the NMDA receptor complex. Orally administered d-serine has been studied clinically as an adjuvant therapeutic intervention in schizophrenia. Thus, we were surprised at its inability to potentiate MK-801's antiseizure efficacy in either control or stressed animals. These data do not support the development of d-serine as a viable therapeutic intervention for schizophrenia and, possibly, other disorders.

Animals↗
PubMed2006

Faulty regulation of tau phosphorylation by the reelin signal transduction pathway is a potential mechanism of pathogenesis and therapeutic target in Alzheimer's disease.

Hyperphosphorylated tau protein is the basic structural component of the neurofibrillary tangle, a histopathological hallmark of Alzheimer's disease. The formation of hyperphosphorylated tau protein may impair learning and the synaptic plasticity of neurons. Tau is a protein that is associated with and stabilizes microtubules; hyperphosphorylated tau protein is unable to perform this stabilization function. The transduction of reelin, a protein that is crucial to neuronal migration and the formation of synaptic connections in the fetal brain, may have an equally important role in regulating at least some forms of learning and synaptic plasticity in the fully developed mature brain. Reelin transduction is mediated by receptors in the brain that are members of the superfamily of low-density lipoprotein receptors. An important downstream target of reelin signal transduction appears to be inhibition of an enzyme involved in the regulation of tau phosphorylation. The faulty transduction of the reelin signal may be a pathological mechanism leading to hyperphosphorylation of tau protein. Ultimately, inhibition of tau phosphorylation may be an important therapeutic target in Alzheimer's disease and other neuropsychiatric disorders.

Alzheimer Disease↗
PubMed2005

Therapeutic implications of a selective alpha7 nicotinic receptor abnormality in schizophrenia.

A convergence of preclinical pharmacology, and human autopsy and genetic data support the existence of reduced expression and function of the alpha7 nicotinic receptor in patients with schizophrenia. The alpha7 nicotinic receptor is a member of a family of ligand-gated ion channels. The alpha7 nicotinic receptor may play an essential role in auditory sensory gating and voluntary smooth pursuit eye movements, two psychophysiological functions that are abnormal in patients with schizophrenia and closely related unaffected biological relatives. Diminished expression or function of the alpha7 nicotinic receptor in schizophrenia has stimulated consideration of selective full or partial alpha7 nicotinic receptor agonists as possible therapeutic interventions for this disorder. Further, the availability of positive allosteric modulators of nicotinic receptors that can improve the efficiency of transduction of the acetylcholine signal and prevent the rapid desensitization of the receptor should encourage these novel treatment approaches (e.g., galantamine).

Eye Movements↗
PubMed2004

Anabasine, a selective nicotinic acetylcholine receptor agonist, antagonizes MK-801-elicited mouse popping behavior, an animal model of schizophrenia.

The expression of the alpha7-nicotinic acetylcholine receptor is diminished in selected brain areas of patients with schizophrenia. This diminished expression may account for the pathophysiological deficits of sensory inhibition and smooth pursuit eye movement performance in these patients. Furthermore, the deficits in sensory inhibition and smooth pursuit eye movement performance in schizophrenia appear to be inherited in an autosomal dominant fashion; thus, the "alpha7-nicotinic acetylcholine receptor-deficiency" may be a necessary condition for expression of schizophrenia. This deficit has encouraged speculation about the possible therapeutic benefit of selective alpha7-nicotinic acetylcholine receptor agonist interventions in this disorder. In view of this, we sought to examine the effect of anabasine, a selective alpha7-nicotinic acetylcholine receptor agonist, on popping behavior in mice elicited by MK-801. MK-801, a high affinity analogue of phencyclidine (PCP), is a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that binds to the hydrophobic domain of this ligand-gated channel. PCP is known to precipitate a schizophreniform psychosis in susceptible individuals, causing productive (e.g. hallucinations) deficit (e.g. affective blunting, amotivation, and social withdrawal), cognitive and motor symptoms similar to those seen in naturally-occurring schizophrenia. Behaviors elicited by MK-801 in mice reflect a pharmacologically-induced state of NMDA receptor hypofunction (NRH), which has been proposed to exist in schizophrenia. Compounds that attenuate MK-801-elicited behaviors, which are identified in this animal model, may have the potential to treat schizophrenia, including deficit and cognitive symptoms. In the current study, anabasine attenuated MK-801-elicited popping at a dose that did not cause clonic seizures. The development of alpha7-nicotinic acetylcholine receptor agonist interventions for schizophrenia must consider their potential liability to elicit seizure activity.

Anabasine↗
PubMed2004

A quantitative measure of postural sway deficits in schizophrenia.

Clinicians rely on observational methods to assess obvious signs of postural abnormalities in schizophrenia, yet subtle signs of postural deficits may go unnoticed. Posture is controlled, in large part, by the cerebellum, which has been implicated in numerous reports of structural and functional deficits in schizophrenia. Given the possibility of an underlying disruption of cerebellar function in schizophrenia, this study used an objective, quantitative measure to assess the magnitude of postural stability in this disorder. A total of 36 schizophrenia patients and 36 non-psychiatric age-matched controls stood on a pressure-sensitive platform that recorded shifts in weight (body sway) through pressure points in the feet. Patients demonstrated more postural sway than did healthy controls (p<0.01). When patients with noticeable signs of tardive dyskinesia were removed from analyses, group differences remained (p<0.01). There was no significant correlation between neuroleptic medication level and degree of postural sway (r=0.16, p=0.37). These results indicate that patients with schizophrenia have subtle, yet quantifiable, disturbances in the control of posture and balance. Quantitative measures of postural sway may provide a more sensitive means of detecting disturbances of movement than do standard clinical observations alone.

Adult↗
PubMed2004

Behavioral consequences of methyllycaconitine in mice: a model of alpha7 nicotinic acetylcholine receptor deficiency.

Diminished expression of the alpha(7) nicotinic acetylcholine receptor occurs in selected brain regions of patients with schizophrenia, which may account for pathophysiological abnormalities and some of the deficits in attention and information processing. In view of this neurotransmitter receptor deficit, we wished to characterize the behavioral consequences associated with the administration of methyllycaconitine (MLA), a competitive alpha(7) nicotinic acetylcholine receptor antagonist, in mice. In this study, we injected groups of 12 outbred NIH Swiss male mice intraperitoneally with MLA (1.0, 3.2 and 10.0 mg/kg) and its saline vehicle. Thereafter, individual mice were observed over a one-hour interval and the intensity of a variety of behaviors were rated on a 4-point scale. The observed behaviors included: gnawing/chewing, rearing, grooming, sniffing, climbing, Straub tail, locomotion and ataxia. MLA produced statistically significant changes in the following observed behaviors: rearing, sniffing, climbing, and locomotion. A profile of the behavioral changes related to MLA administration in mice could lead to the development of a screening paradigm for alpha(7) nicotinic acetylcholine receptor agonist interventions. Ideally, an effective alpha(7) nicotinic acetylcholine receptor agonist intervention would target domains of psychopathology, especially cognitive symptoms that contribute to the profound functional disability that is often associated with schizophrenia.

Aconitine↗
PubMed2004

The "Yoking" of glutamatergic brain mechanisms involved in controlling brain neuronal excitability and psychosis to brain mechanisms involved in appetite regulation: a new hypothesis on the origin of psychosis.

The authors speculate that the human primate evolved psychosis generating brain mechanisms in the service of certain feeding behaviors (i.e., appetite, foraging) during the course of evolution. Furthermore, these "psychosis generating brain mechanisms" may have grown directly out of brain mechanisms servicing appetite, of which neuropeptide Y (NPY) played an important role. A case is made for an NPY contribution to the pathophysiology of psychosis. We hypothesize that the psychomimetic effects of NPY extend to supporting certain "psychomotor" functions that might have been useful for obtaining food resources in "stressful environments" (potentially food resource rich/predator-competitor dangerous). The "psychomotor" functions proposed include helping the evolving ancestral human primate overcome behavioral inhibitions and fears related to venturing into "stressful environments" (potentially food resource rich/predator-competitor dangerous) after their home ranges had been stripped of resources, by providing feelings of decreased anxiety (anxiolysis), infatigability, and, perhaps, even grandiose delusions of physical ability and supernatural supports. We further speculate that it is this NPY mechanism that in part becomes dysregulated in idiopathic psychotic disorders such as schizophrenia. The NPY connection with psychosis could theoretically account for the possible associations between weight changes and antipsychotic response (e.g. [Acta Psychiatr. Scand. 100 (1999) 3] reported by others and body mass index and cocaine-induced psychosis by our group (i.e. [Israel J. Psychiatr. (2004), in submission]).

Affective Disorders, Psychotic↗
PubMed2003

Modulation of MK-801-elicited mouse popping behavior by galantamine is complex and dose-dependent.

The ability of phencyclidine (PCP), a noncompetitive antagonist of NMDA receptor-mediated neurotransmission, to precipitate a schizophreniform psychosis in susceptible individuals is consistent with the hypothesized pathologic occurrence of NMDA receptor hypofunction in this disorder. Because the psychosis caused by PCP resembles schizophrenia in all of the relevant domains of psychopathology, investigators have sought to characterize animal models of NMDA receptor hypofunction. MK-801 (dizocilpine) binds to the same hydrophobic channel domain in the NMDA receptor-associated ionophore as PCP, and has been shown to elicit intense irregular episodes of jumping behavior in mice, termed "popping." MK-801-elicited mouse popping is an animal model of NMDA receptor hypofunction that has been used to screen novel candidate compounds for the treatment of schizophrenia. Recently, a selective abnormality in the transduction of the acetylcholine signal at the level of the alpha 7 nicotinic receptor has been described in schizophrenia. The existence of a nicotinic cholinergic abnormality in schizophrenia has stimulated interest in a potential therapeutic role for positive allosteric modulation of nicotinic receptors. Galantamine is a compound that possesses two interesting properties: inhibition of acetylcholinesterase and positive allosteric modulation of nicotinic neurotransmission. Theoretically, galantamine would be expected to increase the efficiency or likelihood that acetylcholine will promote channel opening and ionic conductance at nicotinic receptors. As expected, in the current investigation statistically significant popping behavior was elicited by MK-801 in mice (T(22) = 2.16, P < 0.05). This MK-801-elicited popping was significantly attenuated by 100 mg/kg of galantamine (T(22) = 2.24, P < 0.05). The data show that nicotinic interventions can influence NMDA receptor-mediated neurotransmission in the intact mouse.

Animals↗
PubMed2003

Interaction of stress and strain on glutamatergic neurotransmission: relevance to schizophrenia.

Psychosis caused by phencyclidine (PCP) stimulated interest in characterizing rodent behaviors elicited by PCP and its analogues. We have shown that MK-801 antagonizes electrically precipitated seizures (defined as tonic hindlimb extension) and elicits episodes of intense jumping behavior, referred to as "popping," in mice. Moreover, 24 h after stress, MK-801's ability to antagonize electrically precipitated seizures is reduced in outbred NIH Swiss mice. Inbred BALBc mice are more resistant to electrically precipitated seizures than the NIH Swiss strain, and are more sensitive to both MK-801's anticonvulsant effect and ability to elicit popping. In the current experiments, we examined the influence of stress and genetic mouse strain on both MK-801's ability to antagonize electrically precipitated seizures and elicit popping. Stress significantly reduced the threshold voltage for precipitation of seizures in BALBc mice and the anticonvulsant properties of MK-801 in both strains. These data show that factors relevant to schizophrenia and its exacerbation (i.e., acute stress and genetics) influence N-methyl-D-aspartic acid (NMDA) receptor-mediated neurotransmission in intact mice. The BALBc inbred strain of mouse may possess advantages in preclinical screening paradigms designed to assess NMDA receptor agonist interventions for disorders such as schizophrenia. Specifically, stressed BALBc mice showed the greatest behavioral sensitivity to MK-801 with regard to electrically precipitated seizures in the incremental electroconvulsive shock (IECS) paradigm, whereas unstressed BALBc showed the greatest behavioral sensitivity to MK-801 in the "popping" paradigm, relative to BALBc and NIH Swiss mice in the appropriate comparison conditions.

Animals↗
PubMed2002

Topiramate antagonizes MK-801 in an animal model of schizophrenia.

The phencyclidine (PCP) model of schizophrenia suggests that N-methyl-D-aspartate (NMDA) receptor hypofunction and its consequences may play an important role in the pathophysiology of this psychiatric disorder. Moreover, the schizophreniform psychosis caused by PCP resembles schizophrenia in all of the relevant domains of psychopathology, especially negative symptoms and cognitive dysfunction. Because of interest in the PCP model and possible NMDA receptor hypofunction in schizophrenia, animal behaviors elicited by PCP and its analogues have been characterized. These preclinical models may serve to identify candidate compounds that possess therapeutic efficacy in schizophrenia. Ideally, negative symptoms and cognitive dysfunction would also serve as therapeutic targets for these novel medications. In the current study, the ability of topiramate to attenuate the severity of a specific behavior elicited by MK-801 (dizocilpine), a high affinity analogue of PCP was studied in mice. Topiramate was chosen because it addresses two of the predicted pathological consequences of NMDA receptor hypofunction. Specifically, topiramate potentiates GABAergic neurotransmission and antagonizes the excitotoxic actions of glutamate at the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) classes of glutamate-gated channels. Topiramate was shown to inhibit MK-801-elicited "popping" behavior in a complex dose-dependent manner.

Animals↗
PubMed2002

Source monitoring in alcoholism.

Recent research on the neural bases of source memory suggests that this type of memory is relevant to the neuropsychological assessment of neurobehavioral disorders. Source memory refers to the ability to discriminate the origin or source of information (e.g., did I think of the idea or did I read about it). We examined source monitoring in abstinent alcoholic patients (N = 53) and nonalcoholic controls (N = 34) and report significant impairments in the alcoholic patients' ability to remember the source of recently presented information. Decrements in source memory were uncorrelated with alcoholic patients' neuropsychological deficits on the Wisconsin Card Sorting Test or the Benton Facial Recognition Test. Using qualitative measures of brain CT scans in a subsample of 39 alcoholic patients, we found that source memory was correlated with Sylvian fissure ratings in the left hemisphere. We propose that source memory decrements are another area of neuropsychological functioning affected in chronic alcoholism. Tasks of source memory may offer the neuropsychologist a valuable new tool for evaluating cognitive functions in neurobehavioral disorders.

Adult↗
PubMed2002

Configural processing in face recognition in schizophrenia.

INTRODUCTION: There is currently substantial literature to suggest that patients with schizophrenia are impaired on many face-processing tasks. This study investigated the specific effects of configural changes on face recognition in groups of schizophrenia patients. METHODS: In Experiment 1, participants identified facial expressions in upright faces and in faces inverted from their upright orientation. Experiments 2 and 3 examined recognition memory for faces and other non-face objects presented in upright and inverted orientations. Experiment 4 explored recognition of facial identity in composite images where the top half of one face was fused to the bottom half of another face to form a new face configuration. RESULTS: In each experiment, the configural change had the same effect on face recognition for the schizophenia patients as it did for control participants. Recognising inverted faces was more difficult than recognising upright faces, with a disproportionate effect of inversion on faces relative to other objects. Recognition of facial identity in face-halves was interfered with by the formation of a new face configuration. CONCLUSION: Collectively, these results suggest that people with schizophrenia rely on configural information to recognise photographs of faces.

Journal Article↗
PubMed2002

Repetitive transcranial magnetic stimulation treatment of comorbid posttraumatic stress disorder and major depression.

Twelve patients with comorbid posttraumatic stress disorder (PTSD) and major depression underwent repetitive transcranial magnetic stimulation (rTMS) to left frontal cortex as an open-label adjunct to current antidepressant medications. rTMS parameters were as follows: 90% of motor threshold, 1 Hz or 5 Hz, 6,000 stimuli over 10 days. Seventy-five percent of the patients had a clinically significant antidepressant response after rTMS, and 50% had sustained response at 2-month follow-up. Comparable improvements were seen in anxiety, hostility, and insomnia, but only minimal improvement in PTSD symptoms. Left frontal cortical rTMS may have promise for treating depression in PTSD, but there may be a dissociation between treating mood and treating core PTSD symptoms.

Adult↗
PubMed2002

Fluoxetine's effects on cognitive performance in patients with traumatic brain injury.

OBJECTIVE: There are preclinical data showing that fluoxetine stimulated expression of Brain Derived Neurotrophic Factor (BDNF) and its specific tyrosine kinase receptor, and caused neuritic elongation and increased dendritic branching density of CA3 hippocampal pyramidal cell neurons in rodents. The latter effect of fluoxetine has been referred to as neuronal remodeling. In view of this preclinical data, we wondered if specific cognitive measures could serve as novel therapeutic targets for fluoxetine in head-injured patients. Theoretically, fluoxetine-induced "neuronal remodeling" might improve cognition, independently of a primary effect on mood. METHOD: In an open-label pilot investigation, fluoxetine hydrochloride (Prozac; 20-60 mg/day) was administered to a heterogeneous group of five head-injured patients with either no or moderate depression for a period of eight months. These patients had no histories of prior treatment with antidepressant medications. They were administered cognitive and memory tests at baseline and after eight months of treatment on fluoxetine. RESULTS: The preliminary results showed that fluoxetine improved mood, in addition to improving performance on the Trail Making Test Part A, an attentional-motor speed task, and the letter-number sequencing subtest of the WAIS-III, a measure reflecting "working memory." CONCLUSIONS: Although fluoxetine had beneficial effects on some measures of cognition, more work is needed to connect these improvements with neuronal remodeling.

Aged↗