Violent persons with schizophrenia and comorbid disorders: a functional magnetic resonance imaging study.

The main goal of this functional Magnetic Resonance Imaging (fMRI) study was to verify the hypothesis that seriously violent persons with Sz and the co-morbid diagnoses of an Antisocial Personality Disorder (APD) and a Substance Use Disorder (Sz+APD+SUD) would present a different pattern of prefrontal functioning than seriously violent persons with Sz only. In support with the main hypothesis, frontal basal cortices were significantly less activated in persons with Sz+APD+SUD during the execution of a go/no-go task than in persons with Sz only and non-violent persons without a mental illness. In contrast, significantly higher activations in frontal motor, premotor and anterior cingulate regions were observed in the Sz+APD+SUD group than in the Sz-only group.

Characteristics and circumstances of homicidal acts committed by offenders with schizophrenia.

BACKGROUND: While men with schizophrenia are at higher risk of displaying homicidal behaviours compared with the general population, very little is known about the circumstances related to the triggering of such violent acts among offenders with schizophrenia. The main goal of the present investigation was to describe the surrounding context, psychotic symptoms, target characteristics and other circumstantial factors associated with homicidal acts committed by men with schizophrenia, with or without an additional antisocial personality disorder (APD). METHOD: Comprehensive clinical and research interviews, as well as multiple sources of information including reports from social workers and police officers, criminal records, witness statements and questionnaires completed by friends, acquaintances and family members were used to determine specific characteristics surrounding the homicidal acts. RESULTS: Overall, a significant majority of homicides were considered as the consequence of psychotic symptoms; they mostly involved someone who knew the offender; and they usually occurred in a private residence. However, the subgroup of offenders with both schizophrenia and APD were less likely to be judged as responding to psychotic symptoms; they assaulted a non-relative more frequently, and they were more likely to have used alcohol and to be involved in an altercation with the victim prior to the incident than offenders without APD. CONCLUSION: Even for such extreme acts as homicides, the circumstances affecting the occurrence of violence among offenders with schizophrenia may differ when an additional APD diagnosis is present, which would have important implications for prevention and treatment programmes.

Effects of dentate nucleus lesions on spatial and postural sensorimotor learning in rats.

The role of the dentate nucleus on spatial orientation, assessed by the Morris water maze test, and on postural sensorimotor performance, assessed by vertical grid, suspended wire, and rotorod tests, was investigated. Bilateral electrolytic lesions of the dentate nucleus slowed down the acquisition of the hidden platform task of the Morris water maze, without affecting long-term retention, the probe trial, and the visuomotor guidance necessary for swimming toward a visible goal. In addition, reversal learning was impaired in the submerged platform condition. The lesions did not affect any of the motor performance scores. The selective impairment seen during acquisition of the hidden platform task is similar to that previously reported in rats with combined lesions of the cerebellar hemispheres and dentate, indicating a specific role for this region in spatial orientation.

Longitudinal age-related changes in motor activities and spatial orientation in CD-1 mice.

Female CD-1 mice were evaluated on three occasions over a nineteen month span in tests of exploration, motor coordination, and spatial orientation in a water maze. Aging decreased motor activity and exploration of specific environmental stimuli found in a hole-board and in a T-maze. Age-related deficits were also found in three motor coordination tasks (inclined grid, coat-hanger, and round bridge) and during retention but not acquisition of the hidden platform version of the water maze task. Performance on some motor coordination tests was linearly correlated with either motor activity or exploration, implying the existence of similar neurobiological pathways responsible for these age-related changes.

A revolving food pellet test for measuring sensorimotor performance in rats.

A revolving food pellet (RFP) test is presented, measuring the ability of rats to eat food pellets suspended from a horizontal bar in their home cage. This easy to make and economical device evaluates the efficiency of bilateral front paw coordination while standing. During the beginning of a ten day testing period, rats exposed to the RFP chamber had a lower intake of food and decreased body weight than rats housed in a standard home cage. With continued practice, the experimental group increased their food intake and body weight. During this time, the rats learned to control the revolving pellets by stabilizing them with their front paws and chewing on them. This apparatus is suitable for assessing a form of sensorimotor learning, involving the efficiency of front paw reaching, grasping, and holding movements, together with appropriate postural adjustments and biting movements. This test was sensitive to brain lesioning, as rats with bilateral lesions of the cerebellar fastigial nucleus were impaired.

Effects of sodium azide on motor activity, motor coordination, and learning.

Because of the proposed importance of cytochrome oxidase in some neurological disorders, an inhibitor of this enzyme was evaluated in a battery of tests measuring exploration, motor coordination, and learning. Mice injected with sodium azide (6 or 12 mg/kg) were slower to initiate a response in a T maze and had less rears in a small chamber than mice injected with placebo. Drugged mice did not alternate spontaneously even at a minimal retention interval (0 min), but were not impaired in water maze spatial and visual discrimination learning tasks. No group differences emerged in terms of horizontal motor activity and its habituation, number of grooming episodes, and motor coordination. These results indicate that azide-induced slowing of motor activity is situation-specific and is accompanied by abnormalities in choice behavior in a T maze.

Effects of midline and lateral cerebellar lesions on motor coordination and spatial orientation.

Rats were lesioned in the midline cerebellum, comprising the vermis and fastigial nucleus, or the lateral cerebellum, comprising the cerebellar hemispheres and dentate nucleus, and evaluated in a series of motor and non-motor learning tests. Rats with midline lesions had difficulty in maintaining their equilibrium on a bridge and were slower before turning upward and traversed less squares on an inclined grid. They were not impaired for muscle strength when suspended from a horizontal wire. Rats with lateral lesions had milder deficits on the bridge and were not affected in the other two tests. In the Morris water maze test, rats with lateral lesions were deficient in spatial orientation, whereas rats with midline lesions were deficient in visuomotor coordination. Lateral lesions had no effects on visual discrimination learning. These results illustrate the differential influence of midline as opposed to lateral cerebellar regions on both motor and non-motor behaviors. Fastigial nucleus lesions decreased the time spent in equilibrium and latencies before falling on the bridge and the distance travelled along the inclined grid but had no effect on muscle strength when suspended from the horizontal string. Quadrant entries and escape latencies were higher in rats with fastigial lesions during the hidden platform condition of the Morris water maze but not during the visible platform condition. It is concluded that fastigial-lesioned rats are impaired in equilibrium and spatial orientation but with repeated trials learn to improve their performances.

Dorsal striatal lesions in rats. 1: Effects on exploration and motor coordination.

Rats with small dorsal striatal lesions were compared to sham-operated controls in a series of test measuring their exploratory behavior in a T-maze, a hole-board, and an elevated plus-maze. Motor coordination was evaluated in the inclined grid and in the square bridge tests and grip strength in the wire suspension test. The rats with dorsal striatal lesions were not impaired in the motor coordination tests, the grip strength test, nor in spontaneous alternation. By contrast, an increase of emergence latencies in the elevated plus-maze and a reduction of motor activity in the hole-board confined space during the early part of testing were observed in rats with dorsal striatal lesions. These results are ascribed to a lesion-induced situation-specific increase in inhibition.

Dorsal striatal lesions in rats. 2: Effects on spatial and non-spatial learning.

Rats with small electrolytic lesions of the dorsal striatum were evaluated in acquisition of spatial learning, sensorimotor learning, and a straight runway food approach response and its extinction. No differences were detected between rats with dorsal striatal lesions and sham-operated controls during acquisition of hidden and visible trials in the Morris water maze. Neither was an intergroup difference observed during acquisition of the rotorod test of motor coordination. Lesioned rats were not impaired in running for a food reward, but their running latencies on day 2 of extinction were lower than those of controls, an indication of perseveration. These results indicate that perseverative responding may occur in dorsal striatal lesioned rats in the absence of spatial or sensorimotor defects.

Beam sensorimotor learning and habituation to motor activity in lurcher mutant mice.

Lurcher mutant mice lose cerebellar granule cells and Purkinje cells. The mutants were compared to normal mice in a beam-walking task. Normal mice were placed on a slippery bridge while lurchers, because of their severe ataxia, were placed on a bridge with the same diameter, but enveloped with surgical tape to improve traction. The performance of both groups improved with repeated trials. In an activity box, lurcher mutants were as active as normal mice, showed normal intrasession habituation, and emerged from a toy object as easily as normal mice. These results indicate that the cerebellar damage in lurchers does not prevent the acquisition of a motor skill task requiring balance in an immobile apparatus. Ataxia was not accompanied by hypoactivity, inhibition or disturbances in intrasession habituation.

Exploration and motor coordination in dystonia musculorum mutant mice.

Dystonia musculorum (dt) mutant mice, characterized by degeneration of spinocerebellar tracts, were impaired in terms of horizontal and vertical motor activity, hole poking, exploration, and motor coordination. In tests of motor coordination, their deficits were more severe than those of previously tested mutant mice with degeneration of cerebellar cells. However, unlike other cerebellar mutants, dt mutants alternated above chance levels in a two-trial spontaneous alternation test, which is a test of inhibitory tendencies and spatial orientation, and so dt mutants may not be impaired in these functions.

Are age-related behavioral disorders improved by folate administration?

In this brief review of the possible link between age-related behavioral disorders and brain folate levels, preliminary data on humans and animals are presented. These data indicate that folate administration may improve some age-related behavioral dysfunctions. In aged humans and rats, there is a defect in the absorption of dietary folate, leading perhaps to a decrease in brain folate levels. If so, folate therapy may replenish brain stores of folates and may reverse some age-related behavioral deficits. Some questions concerning the possible relationship among mood status, intellectual functions, and folate levels in aging are discussed.

Simultaneous visual discrimination learning in lurcher mutant mice.

Lurcher mutants were evaluated in the acquisition of a visual discrimination learning task with water escape as a reward. In comparison to normal mice, lurchers were impaired in discrimination learning in a manner not explainable by motor deficits. Although in initial trials the mutants had difficulty in finding the correct invisible platform, in agreement with previous findings of deficits in visuo-spatial organization, they eventually were able to find the quadrants where one of two platforms was situated but even so took longer to reach criterion in choosing the correct one. These results agree with the hypothesis that the cerebellum is involved in the acquisition of visual discrimination tasks in mice.

Swimming activity in dystonia musculorum mutant mice.

Dystonia musculorum (dt) mutant mice, characterized by degeneration of spinocerebellar fibers, were evaluated in a visible platform swim test. It was found that dt mutants were slower to reach the platform than normal mice. However, the number of quadrants traversed was not higher in dt mutants. It is concluded that spinocerebellar fibers to the vermis are important in limb control during swimming but not in visuo-motor guidance (navigational skills) of the animal towards a visible goal, at least in regard to the quadrant measure. It is not excluded that a measure tracing their path may find a mild deviation from the goal.

Hole poking and motor coordination in lurcher mutant mice.

Lurcher mutant mice, a cerebellar mutant displaying ataxia and equilibrium deficits, had fewer hole pokes in a 16-hole matrix than normal mice. Lurcher mutants also took longer to reach a platform from a grid and to begin to climb a grid from the floor. However, the lurchers climbed as high as normal mice on the grid and their exploratory patterns of the holeboard were similar in many respects to normal mice, such as the ratio of center to peripheral hole exploration. In a wooden beam test, although lurchers did not differ from normal mice in terms of the amount of time spent on the beam or in the distance travelled, the mutants were found more often in unstable positions.

Effects of ketamine and L-glutamic acid diethyl ester on spatial and nonspatial learning tasks in rats.

An NMDA antagonist, ketamine, at the highest dose tested (15 mg/kg), impaired the acquisition of a hole-board spatial learning task but not the acquisition of a left-right alternation task. A non-NMDA (quisqualate) antagonist, L-glutamic acid diethyl ester (LGDE), did not impair the acquisition of either task. Both drugs had effects on different aspects of a go-no go discrimination task and a straight runway task, ketamine tending to activate and LGDE tending to slow rats. These results concur with previous research regarding the sensitivity of some spatial tasks to NMDA antagonism. Non-NMDA antagonists affect behavior without causing spatial deficits.

Effects of folic acid and folinic acid on cognitive and motor behaviors in 20-month-old rats.

Old rats had lower plasma concentrations of folates but not of vitamin B12 than young rats. Old rats injected with pharmacological doses of folic acid (5 mg/kg) or folinic acid (2.5 mg/kg) every 2 days for a 32-day period spontaneously alternated above chance levels at the 0-min retention interval whereas old rats injected with placebo did not. Rats injected with folinic acid that had plasma folate concentrations above the median for that group alternated at the 3-min retention interval whereas none of the other subgroups did. These results indicate that supplementation with folinic acid at pharmacological doses may decrease perseverative responding and improve spatial memory in old rats. However, neither vitamin group was improved in motor coordination, grip strength, or spatial learning in a water maze. There was no hyperactivity or loss of body weight following vitamin supplementation.

Amantadine and ketamine-induced improvement of motor coordination in lurcher mutant mice.

The effects of amantadine and ketamine were compared to a placebo in a coat-hanger test on lurcher mutant mice. This test measures motor coordination and is dependent on cerebellar functioning. Both drugs improved motor coordination of the cerebellar mutants in that the time taken to reach the side-bar according to a 2 paw criterion was decreased during the drugged condition in comparison to the non-drugged condition. This result indicates that NMDA receptor antagonists may improve motor coordination in animals with cerebellar disease.

Motor abnormalities in lurcher mutant mice.

Lurcher mutants had deficits in equilibrium in the coat-hanger and grid tests but not the wooden beam test. Although the mutants had less hole-pokes when confronted with small holes in most conditions, they had more hole-pokes with larger holes, demonstrating perseverative behavior. There was no decrease in rearing responses. These results indicate that in spite of cerebellar degeneration and ataxia, lurcher mutants are not impaired in all tests measuring motor function.

Effects of ketamine and 1-glutamic acid diethyl ester on concept learning in rats.

The effects of ketamine, an NMDA receptor antagonist, and 1-glutamic acid diethyl ester (LGDE), a non-NMDA glutamate antagonist, were evaluated in the acquisition of concept learning in a water maze. In concept learning, the rats must locate an invisible platform whose location changes from day to day. In spatial learning (Morris task), the rats must locate an invisible (or visible) platform whose location does not change. Ketamine increased quadrant entries at 5, 10 and 20 mg/kg, and latencies at 10 and 20 mg/kg on the final two days of training on the concept task. At 5 mg/kg ketamine disrupted concept learning but not spatial learning or visuo-motor coordination as assessed by invisible and visible platform conditions of the Morris maze. Progressively higher doses of ketamine affected first the invisible condition and then the visible platform condition. On the other hand, LGDE did not affect the Morris task at any dose. However, there was no decrease in latencies over days in concept learning at the two highest doses (240 and 360 mg/kg) of LGDE. Thus LGDE appeared to slow down decision time in the concept task but not the spatial task in the absence of an effect on quadrant entries in any version. These results indicate that NMDA receptors are involved in spatial and concept learning. Non-NMDA receptors appear to be involved only in concept learning.