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Visuospatial perception, construction and memory in alcoholism.

OBJECTIVE: To analyze visuospatial cognition in recently detoxified alcoholics from the perspectives of three ways of conceptualizing spatial information processing: egocentric versus allocentric orientation, featural versus configural analysis, and categorical versus coordinate spatial judgements. METHOD: Twenty-eight chronic alcoholics (19 men, 9 women) were compared to 20 (10 men, 10 women) controls of comparable age and education on a battery of tests of visuospatial scanning, construction, mental imagery, and anterograde and remote spatial memory. Tests were administered 21-40 days after alcoholics entered treatment. RESULTS: Alcoholics displayed impairment in visuospatial scanning, construction, utilizing and manipulating information from visual images and on three tests of anterograde spatial memory, but remote spatial memory was not significantly affected. Their deficits were evident on some measures of allocentric orientation, featural and configural analysis, but consistent deficits on egocentric orientation or categorical or coordinate spatial judgments were not seen. CONCLUSIONS: Deficits in spatial cognition exhibited by alcoholics do not seem to arise from dysfunction in any localized brain region. Small but potentially important impairments in fundamental aspects of spatial information processing such as scanning and use of visual imagery were found. The empirical basis and clinical significance of these deficits requires further study.

Adult↗

Phencyclidine affects memory in a nitric oxide-dependent manner: working and reference memory.

Phencyclidine (PCP), a non-competitive NMDA receptor antagonist, was used to model schizophrenia-like cognitive dysfunctions of learning and memory in rats using the Morris water maze model for spatial memory. A protocol introduced by Baldi and co-workers was used to distinguish working memory from reference memory. Male Sprague-Dawley rats were administered PCP (2.0 mg/kg) before the first swimming trial on each of five spatial memory acquisition days, either alone or after pre-treatment with the nitric oxide synthase inhibitor, L-NAME (10 mg/kg). Probe tests for memory were conducted before and after each acquisition session. The results showed that PCP disrupted the acquisition of both working and reference memory. Pre-treatment with L-NAME reversed both these effects of PCP. L-NAME treatment by itself did not significantly alter either acquisition or retention of spatial memory.

Analysis of Variance↗

A unified model of spatial and episodic memory.

Medial temporal lobe structures including the hippocampus are implicated by separate investigations in both episodic memory and spatial function. We show that a single recurrent attractor network can store both the discrete memories that characterize episodic memory and the continuous representations that characterize physical space. Combining both types of representation in a single network is actually necessary if objects and where they are located in space must be stored. We thus show that episodic memory and spatial theories of medial temporal lobe function can be combined in a unified model.

Animals↗

Prefrontal task-related activity representing visual cue location or saccade direction in spatial working memory tasks.

To examine what kind of information task-related activity encodes during spatial working memory processes, we analyzed single-neuron activity in the prefrontal cortex while two monkeys performed two different oculomotor delayed-response (ODR) tasks. In the standard ODR task, monkeys were required to make a saccade to the cue location after a 3-s delay, whereas in the rotatory ODR (R-ODR) task, they were required to make a saccade 90 degrees clockwise from the cue location after the 3-s delay. By comparing the same task-related activities in these two tasks, we could determine whether such activities encoded the location of the visual cue or the direction of the saccade. One hundred twenty one neurons exhibited task-related activity in relation to at least one task event in both tasks. Among them, 41 neurons exhibited directional cue-period activity, most of which encoded the location of the visual cue. Among 56 neurons with directional delay-period activity, 86% encoded the location of the visual cue, whereas 13% encoded the direction of the saccade. Among 57 neurons with directional response-period activity, 58% encoded the direction of the saccade, whereas 35% encoded the location of the visual cue. Most neurons whose response-period activity encoded the location of the visual cue also exhibited directional delay-period activity that encoded the location of the visual cue as well. The best directions of these two activities were identical, and most of these response-period activities were postsaccadic. Therefore this postsaccadic activity can be considered a signal to terminate unnecessary delay-period activity. Population histograms encoding the location of the visual cue showed tonic sustained activation during the delay period. However, population histograms encoding the direction of the saccade showed a gradual increase in activation during the delay period. These results indicate that the transformation from visual input to motor output occurs in the dorsolateral prefrontal cortex. The analysis using population histograms suggests that this transformation occurs gradually during the delay period.

Animals↗

Exploring the temporal dynamics of the spatial working memory n-back task using steady state visual evoked potentials (SSVEP).

The neural networks associated with spatial working memory (SWM) are well established. However, the temporal dynamics of SWM-related brain activity are less clear. This study examined changes in temporal neurophysiology during the spatial n-back task using steady state probe topography (SSPT) to record cortical steady state visual evoked potentials (SSVEPs) at 64 scalp locations. Twenty healthy male volunteers participated in the study. The findings identified three different time periods of significance during the spatial n-back task--an early perceptual/encoding period (approximately 0-500 ms), an early delay period just following the stimulus disappearing from view (approximately 850-1400 ms), and a late period lasting the final second of the delay and anticipation of the new stimulus (approximately 2500-3500 ms). The delay period was associated with increases in frontal and occipital region amplitude, consistent with previous findings in more basic working memory tasks. The two different SSVEP components during the delay appear reflective of the additional "executive" demands associated with the n-back and may suggest variable roles for the PFC during different stages of the delay. All three n-back levels demonstrated a relative consistent electrophysiological profile, indicating that this pattern is specific to the spatial n-back task. Nevertheless, these findings supported the hypothesis that memory load modulates activity within the networks identified, consistent with previous neuroimaging studies. The current findings may offer a framework in which to further investigate the temporal aspects of SWM.

Adult↗

Role of alpha2C-adrenoceptor subtype in spatial working memory as revealed by mice with targeted disruption of the alpha2C-adrenoceptor gene.

The role of the alpha2C-adrenoceptor subtype in mediating the beneficial effect of alpha2-adrenoceptor agonists on spatial working memory was studied in adult mice with targeted inactivation of the alpha2C-receptor gene (KO) and their wild-type controls (WT). A delayed alternation task was run in a T-maze with mixed delays varying from 20 s to 120 s. Dexmedetomidine, a specific but subtype nonselective alpha2-adrenoceptor agonist, dose-dependently decreased the total number of errors. The effect was strongest at the dose of 5 microg/kg (s.c.), and was observed similarly in KO and WT mice. KO mice performed inferior to WT mice due to a higher number of perseverative errors. Dexmedetomidine slowed initiation of the motor response in the start phase at lower doses in WT mice than in KO mice but no such difference was observed in the return phase of the task, suggesting involvement of alpha2C-adrenoceptors in the cognitive aspect of response preparation or in response sequence initiation. According to these findings, enhancement of spatial working memory is best achieved with alpha2-adrenoceptor agonists which have neither agonistic nor antagonistic effects at the alpha2C-adrenoceptor subtype.

Adrenergic alpha-Agonists↗

Impairment of spatial working memory of rats in radial maze performance induced by ethylcholine mustard aziridinium picrylsulfonate (AF64A-P): retention curve analysis.

The effects of the cholinergic neurotoxin, ethylcholine mustard aziridinium picrylsulfonate (AF64A-P), on the spatial working memory in eight-arm radial maze performance were studied. Rats well-trained on radial maze performance were injected intracerebroventricularly with AF64A-P (0.05 nmol/each side) or artificial cerebrospinal fluid (A-CSF, 5 microliters). AF64A-P produced a selective reduction of choline acetyltransferase activity in the hippocampus. Rats treated with AF64A-P showed a significant decrease in the number of correct responses in baseline performance compared to rats injected with A-CSF. To examine whether the deficits might result from the disruption of memory, tests of memory retention were studied. Various delay intervals (45, 90, 180, or 360 min) were interposed between the fourth and the fifth choice, and the number of correct responses in the choices 5-8 were then examined as a function of retention intervals. Significant interaction of deficits in arm-choice accuracy induced by AF64A-P with retention intervals in the choices 5-8 was observed. Oxotremorine, a muscarinic receptor agonist (0.025, 0.05 and 0.1 mg/kg, ip), was able to reverse this deficit in a dose-dependent manner. These observations reveal a pattern of impairment of spatial working memory during prolonged states of central cholinergic hypofunction induced by intracerebroventricular administration of AF64A-P, which binds irreversibly to its receptor site.

Animals↗

Impaired allocentric spatial working memory and intact retrograde memory after thalamic damage caused by thiamine deficiency in rats.

Rats were tested on an allocentric-spatial working-memory task--delayed matching-to-place (DMTP) in a water maze--before and after either pyrithiamine-induced thiamine deficiency (PTD) or electrolytic lesions of the lateral internal medullary laminae (IML), an area damaged by PTD. DMTP trials consisted of paired swims, with the escape platform in a new location on each trial. PTD rats were impaired at retention delays of 300 s, but not at delays of 4 or 60 s. Rats with IML lesions performed normally at all delays. Both groups displayed normal retention of object-discrimination problems that they had learned at different intervals before treatment (5 weeks, 3 weeks, and 1 week). The results suggest that PTD causes delay-dependent deficits of allocentric spatial working memory and that damage outside the IML is probably responsible. Neither PTD-induced diencephalic damage nor restricted IML lesions appear to produce a global retrograde amnesia.

Animals↗

Spatial working memory deficit in unilateral neglect.

Based on the similarity of brain areas lesioned in neglect and those activated by spatial working memory (WM) tasks in normals, we hypothesized that neglect may involve spatial WM impairments. A left neglect patient with right inferior frontal and basal ganglia damage performed cancellation tasks, making either highly visible marks (to provide a reminder of visited items), or invisible marks (so only spatial WM could represent cancelled items). Invisible marks led to repeated cancellations for targets that differed only in location, but not for targets with memorable unique identities, suggesting a deficit of spatial WM, with non-spatial WM spared. Neglect was greater for cancellation with invisible marks, consistent with a role for deficient spatial WM in cancellation deficits, but contrary to account solely in terms of attention capture by salient visible marks made in ipsilesional space.

Attention↗

Spatial working memory performance after high-frequency repetitive transcranial magnetic stimulation of the left and right posterior parietal cortex in humans.

The effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) at the left or right posterior parietal cortex were studied using a spatial working memory task. Eight subjects were stimulated over the P3 and P4 electrode site at 115% of the motor threshold (frequency 25 Hz, trains of 200 ms) during the 1000-ms delay of the spatial working memory task, or received sham stimulation. It was found that the reaction times were slower during right-parietal rTMS than during left-parietal rTMS. No differences were found between the percentages correct responses. These results are in line with recent neuroimaging findings and data from patients with cerebral lesions, suggesting that the posterior parietal cortex is especially involved in spatial processing, and provide converging evidence for recent theories on hemispheric specialization.

Adult↗

Equivalent impairment of spatial and nonspatial memory following damage to the human hippocampus.

The hippocampus has sometimes been proposed to function as a cognitive map, a memory system that stores information about allocentric space. Work with experimental animals and memory-impaired patients has raised difficulties with this view by showing that the hippocampus is not performing an exclusively spatial function. However, the possibility has remained that the hippocampus plays a special role in spatial memory or a disproportionately large role in spatial memory compared to other kinds of memory. This study compared spatial and nonspatial memory in amnesic patients with lesions of the hippocampal formation or diencephalon. Subjects studied an array of 16 toy objects and were subsequently tested for object recall, object recognition, and memory for the location of the objects. Control subjects were tested after long retention intervals in order to equate their object memory performance with that of the patients. The main finding was that, when the performance of amnesic patients on the object memory tests was matched to the object memory performance of control subjects, spatial memory performance of the amnesic patients also matched the spatial memory performance of the control subjects. The results were the same for the two groups of patients. These findings suggest that the hippocampus is not especially involved in spatial memory. Spatial memory is simply one instance of a broader category of memory that requires the hippocampus. While cognitive mapping in its most abstract sense may describe hippocampal function, our results support alternative formulation, suggesting that the hippocampus is necessary for the rapid acquisition of relational, configural, or declarative (as opposed to purely spatial) information.

Adult↗

Noradrenaline and dopamine elevations in the rat prefrontal cortex in spatial working memory.

The role of prefrontal cortical dopamine (DA) in the modulation of working memory functions is well documented, but substantial evidence indicates that the locus ceruleus noradrenergic system also modulates working memory via actions within the prefrontal cortex (PFC). This study shows that PFC noradrenaline (NA) and DA dialysate levels phasically increase when rats perform correctly in a delayed alternation task in a T-maze, a test of spatial working memory. However, NA levels were markedly enhanced in animals trained to alternate compared with rats that acquired the spatial information about the location of food in the maze but were untrained to make a choice to obtain the reward. In contrast, PFC DA elevations occurred independently of whether the animal had acquired the trial-specific information for correct task execution. The contribution of anticipatory responses to catecholamine efflux was also evaluated by exposing rats to an environment signaling the presence of the reward in the successive alternation task. No conditioned NA efflux was observed in either group. In contrast, in both groups, DA efflux increased in the anticipatory phase of the test to the same levels of those reached during the task. These data provide the first direct evidence for a selective activation of PFC NA transmission during a spatial working memory task. We propose that, in the working memory task, DA is primarily associated with reward expectancy, whereas NA is involved in the active maintenance of the information about a goal and the rules to achieve it.

Analysis of Variance↗

Spatial working memory in Asperger's syndrome and in patients with focal frontal and temporal lobe lesions.

Spatial working memory (SWM) was investigated in 15 patients with Asperger's syndrome (AS) comparing their performance to 18 age- and IQ-matched control subjects. An additional comparison was made with 20 unilateral frontal excision patients [9 right (RFL); 11 left (LFL)] and with 38 unilateral temporal lobectomy patients [18 right (RTL); 18 left (LTL)], the frontal and temporal lobe patients having separate matched control groups. SWM was tested using the Executive Golf Task, a test that also measures spatial strategy formation. The AS group showed a substantial deficit on SWM, but no impairment in strategy formation. The LFL showed the same pattern of impairment, but with a less substantial deficit. The RFL group showed a large deficit, but some of this was accounted for by a strategy formation impairment. Of the temporal lobe lesions groups, only the RTL group was impaired on SWM, but this group showed normal strategy formation. It was concluded that the SWM deficit in AS may reflect a more general difficulty in accessing different types of representations in order to guide voluntary behavior, providing at least a partial explanation for the executive deficits found in AS.

Adolescent↗

Effects of histamine on MK-801-induced memory deficits in radial maze performance in rats.

The effects of histamine on the spatial memory deficits induced by MK-801 were investigated using the eight-arm radial maze paradigm in rats. Intracerebroventricular (i.c.v.) injection of histamine or thioperamide, and intraperitoneal (i.p.) injection of histidine improved the spatial memory deficits induced by MK-801. Similar results were obtained with 2-thiazolylethylamine. In contrast, 4-methylhistamine showed no significant effect. Based on these observations, it seems likely that the protective effect of histamine on MK-801-induced spatial memory deficit is mediated by H(1)-receptors.

Analysis of Variance↗

Neural correlates of spatial working memory in humans: a functional magnetic resonance imaging study comparing visual and tactile processes.

Recent studies of neural correlates of working memory components have identified both low-level perceptual processes and higher-order supramodal mechanisms through which sensory information can be integrated and manipulated. In addition to the primary sensory cortices, working memory relies on a widely distributed neural system of higher-order association areas that includes posterior parietal and occipital areas, and on prefrontal cortex for maintaining and manipulating information. The present study was designed to determine brain patterns of neural response to the same spatial working memory task presented either visually or in a tactile format, and to evaluate the relationship between spatial processing in the visual and tactile sensory modalities. Brain activity during visual and tactile spatial working memory tasks was measured in six young right-handed healthy male volunteers by using functional magnetic resonance imaging. Results indicated that similar fronto-parietal networks were recruited during spatial information processing across the two sensory modalities-specifically the posterior parietal cortex, the dorsolateral prefrontal cortex and the anterior cingulate cortex. These findings provide a neurobiological support to behavioral observations by indicating that common cerebral regions subserve generation of higher order mental representations involved in working memory independently from a specific sensory modality.

Adult↗

Effects of the NMDA antagonist MK-801 on radial maze performance in histidine-deficient rats.

We examined the effects of a histidine-deficient diet on brain histamine contents as well as on learning and memory using the eight-arm radial maze in rats. A significant decrease in histamine content in the hippocampus was observed after long-term feeding of rats with a histidine-deficient diet. At the same time, significant enhancement of the acquisition process in radial maze performance was also observed. Pyrilamine did not show a significant effect on radial maze performance in histidine-deficient rats. On the other hand, pyrilamine caused a significant spatial memory deficit in control rats. Scopolamine was effective in inhibiting spatial memory in both histidine-deficient and control rats. MK-801 caused spatial memory deficits more potently in histidine-deficient rats than in controls. Brain glycine contents showed a significant increase in the hippocampus in histidine-deficient rats. These results indicated that the spatial memory deficits induced by MK-801 in histidine-deficient rats are closely related to increased glycine levels and activation of NMDA receptors.

Amino Acids↗

The septohippocampal cholinergic system and spatial working memory in the Morris water maze.

The objective of the present study was to determine whether a systematic optimization of Morris water maze (mwm) testing parameters could reveal a significant role of the septohippocampal cholinergic system in spatial working memory. Young adult rats were lesioned using 192 IgG-saporin infused bilaterally into the medial septum. Lesions were near complete as measured by choline acetyltransferase (ChAT) activity and immunohistochemistry. Behavioral testing was performed in three phases. In the first, lesioned and unlesioned rats were trained in the mwm focusing on working memory, which was tested using novel platform locations daily. In the second phase, the optimal locations were retested with increasing intertrial intervals (ITI). In the third phase, intracerebroventricular infusions of nerve growth factor (NGF) were employed to enhance cholinergic activity of the unlesioned rats and potentially further separate group performance. Neither the standard or increased ITI resulted in a consistent significant difference in spatial working memory between groups. In addition, NGF treatment also failed to induce a significant difference in behavioral performance. In conclusion, impairments in working memory as assessed by the mwm could not be revealed despite a greater than 90% loss of hippocampal ChAT and the use of optimal testing parameters and NGF treatment.

Animals↗

Supranormal stimulation of D1 dopamine receptors in the rodent prefrontal cortex impairs spatial working memory performance.

Although previous research has emphasized the beneficial effects of dopamine (DA) on functions of the prefrontal cortex (PFC), recent studies of animals exposed to mild stress indicate that excessive DA receptor stimulation may be detrimental to the spatial working memory functions of the PFC (Arnsten and Goldman-Rakic, 1990; Murphy et al., 1994, 1996a,b, 1997). In particular, these studies have suggested that supranormal stimulation of D1 receptors may contribute to the detrimental actions of DA in the PFC (Murphy et al., 1994, 1996a). The current study directly tested this hypothesis by examining the effects of infusing a full D1 receptor agonist, SKF 81297, into the PFC of rats performing a spatial working memory task, delayed alternation. SKF 81297 produced a dose-related impairment in delayed-alternation performance. The impairment was reversed by pretreatment with a D1 receptor antagonist, SCH 23390, consistent with drug actions at D1 receptors. SCH 23390 by itself had no effect on performance, although slightly higher doses impaired performance (Murphy et al., 1994, 1996a). There was a significant relationship between infusion location and drug efficacy; animals with cannulae anterior to the PFC were not impaired by SKF 81297 infusions. Taken together, these results demonstrate that supranormal D1 receptor stimulation in the PFC is sufficient to impair PFC working memory function. These cognitive data are consistent with recent electrophysiological studies of D1 receptor mechanisms affecting the PFC (Williams and Goldman-Rakic, 1995; Yang and Seamans, 1996). Increased D1 receptor stimulation during stress may serve to take the PFC "off-line" to allow posterior cortical and subcortical structures to regulate behavior, but may contribute to the vulnerability of the PFC in many neuropsychiatric disorders.

Animals↗