Auditory event-related potentials during a spatial working memory task.

OBJECTIVE: Sensory cortical activity can be jointly governed by bottom-up (e.g. stimulus features) and top-down (e.g. memory, attention) factors. We tested the hypothesis that auditory sensory cortical activity is affected by encoding and retrieval of spatial information. METHODS: Auditory event-related potentials (ERPs) were recorded during working memory and passive listening conditions. Trials contained three noise bursts (two "items" at different locations, followed by a "probe"). In the working memory task subjects determined if the probe matched an item location. The influence of long-term memory was evaluated by training to one location that was always a non-match. Auditory ERPs were analyzed to items and probes (N100, P200, late positive wave-LPW). RESULTS: Reaction times varied significantly among probes (trained non-match

Head direction cells in rats with hippocampal or overlying neocortical lesions: evidence for impaired angular path integration.

Rodents use two distinct navigation strategies that are based on environmental cues (landmark navigation) or internal cues (path integration). Head direction (HD) cells are neurons that discharge when the animal points its head in a particular direction and are responsive to the same cues that support path integration and landmark navigation. Experiment 1 examined whether HD cells in rats with lesions to the hippocampus plus the overlying neocortex or to just the overlying neocortex could maintain a stable preferred firing direction when the rats locomoted from a familiar to a novel environment, a process thought to require path integration. HD cells from both lesion groups were unable to maintain a similar preferred direction between environments, with cells from hippocampal rats showing larger shifts than cells from rats sustaining only cortical damage. When the rats first explored the novel environment, the preferred directions of the cells drifted for up to 4 min before establishing a consistent firing orientation. The preferred direction was usually maintained during subsequent visits to the novel environment but not across longer time periods (days to weeks). Experiment 2 demonstrated that a novel landmark cue was able to establish control over HD cell preferred directions in rats from both lesion groups, showing that the impairment observed in experiment 1 cannot be attributed to an impairment in establishing cue control. Experiment 3 showed that the preferred direction drifted when HD cells in lesioned animals were recorded in the dark. It was also shown that the anticipatory property of anterodorsal thalamic nucleus HD cells was still present in lesioned animals; thus, this property cannot be attributed to an intact hippocampus. These findings suggest that the hippocampus and the overlying neocortex are involved in path integration mechanisms, which enable an animal to maintain an accurate representation of its directional heading when exploring a novel environment.

Auditory brain-stem, middle- and long-latency evoked potentials in mild cognitive impairment.

OBJECTIVE: Mild cognitive impairment (MCI) is a selective episodic memory deficit in the elderly with a high risk of Alzheimer's disease. The amplitudes of a long-latency auditory evoked potential (P50) are larger in MCI compared to age-matched controls. We tested whether increased P50 amplitudes in MCI were accompanied by changes of middle-latency potentials occurring around 50 ms and/or auditory brain-stem potentials. METHODS: Auditory evoked potentials were recorded from age-matched controls (n = 16) and MCI (n = 17) in a passive listening paradigm at two stimulus presentation rates (2/s, 1/1.5 s). A subset of subjects also received stimuli at a rate of 1/3 s. RESULTS: Relative to controls, MCI subjects had larger long-latency P50 amplitudes at all stimulus rates. Significant group differences in N100 amplitude were dependent on stimulus rate. Amplitudes of the middle-latency components (Pa, Nb, P1 peaking at approximately 30, 40, and 50 ms, respectively) did not differ between groups, but a slow wave between 30 and 49 ms on which the middle-latency components arose was significantly increased in MCI. ABR Wave V latency and amplitude did not differ significantly between groups. CONCLUSIONS: The increase of long-latency P50 amplitudes in MCI reflects changes of a middle-latency slow wave, but not of transient middle-latency components. There was no evidence of group difference at the brain-stem level. SIGNIFICANCE: Increased slow wave occurring as early as 50 ms may reflect neurophysiological consequences of neuropathology in MCI.

Sensory cortical interactions in aging, mild cognitive impairment, and Alzheimer's disease.

Progressive declines in memory function accompany normal aging, mild cognitive impairment (MCI), and Alzheimer's disease (AD). Neuropathological studies suggest that damage to neurons providing connections between cortical areas may contribute to memory impairments in AD. Because AD develops slowly, similar neuropathological changes, to a lesser degree, may be present in MCI and some asymptomatic elderly subjects. In this study we tested the hypothesis that corticocortical interactions between sensory regions are impaired in aging, MCI, and AD, as compared with young subjects. When sensory cortical evoked potentials are elicited by pairs of stimuli the amplitudes of potentials to the second stimulus are attenuated. Corticocortical interactions were assessed by presenting stimulus pairs in different modalities (auditory/visual). There were significant group differences in the degree that a visual stimulus attenuated subsequent auditory potentials (young > healthy elderly > MCI > AD). Control experiments indicated equivalent amplitude reductions for all groups to the second stimulus for stimulus pairs having the same modality. These findings are compatible with progressive declines in corticocortical processing in aging, MCI, and AD.

Cue control and head direction cells.

Previous research has shown that head direction (HD) cells in both the anterior dorsal thalamus (ADN) and the postsubiculum (PoS) in rats discharge in relation to familiar, visual landmarks in the environment. This study assessed whether PoS and ADN HD cells would be similarly responsive to nonvisual or unfamiliar environmental cues. After visual input was eliminated by blindfolding the rats, HD cells maintained direction-specific discharge, but their preferred firing directions became less stable. In addition, rotations of the behavioral apparatus indicated that some nonvisual cues (presumably tactile, olfactory, or both) exerted above chance stimulus control over a cell's preferred firing direction. However, a prominent auditory cue was not effective in exerting stimulus control over a cell's preferred direction. HD cell activity also was assessed after rotation of a novel visual cue exposed to the rat for 1, 3, or 8 min. An 8-min exposure was enough time for a novel visual cue to gain control over a cell's preferred direction, whereas an exposure of 1 or 3 min led to control in only about half the sessions. These latter results indicate that HD cells rely on a rapid learning mechanism to develop associations with landmark cues.

On the behavioral significance of head direction cells: neural and behavioral dynamics during spatial memory tasks.

Current theories assume that rats use the directional information reflected by head direction (HD) cells when performing spatial tasks. This assumption was assessed by monitoring anterior thalamic HD cell activity and relating it to the subject's behavioral response on 2 spatial memory tasks that tested either reference memory or working memory. In both tasks, there was a significant number of trials where there was not a tight coupling between the preferred firing direction of HD cells and the direction of the behavioral response. In addition, it was possible to intentionally change the preferred direction of HD cells without affecting performance accuracy. An additional experiment showed that manipulations that affected internal, but not external, cues impaired performance on the reference memory task. These findings suggest that HD cell activity was not consistently guiding the subjects' behavior on these 2 spatial tasks.

Recordings of postsubiculum head direction cells following lesions of the laterodorsal thalamic nucleus.

Areas of the rodent limbic system are important for solving spatial tasks and accurate navigation. Previous studies have identified cells in the postsubiculum (PoS) and the lateral dorsal thalamus (LDN) which discharge as a function of the animal's head direction in the horizontal plane. These two brain areas are reciprocally connected with one another. To determine the contribution of the LDN to the functioning of PoS head direction cells, we lesioned the LDN and recorded single units in the PoS. We report here that lesions of the LDN had little effect upon the firing properties of PoS HD cells. In addition, HD cells from lesioned animals showed normal responses to two environmental manipulations: (1) when the salient visual cue was rotated the preferred firing directions of PoS HD cells shifted a similar amount and (2) cells frequently ceased firing, or had reductions in their peak firing rate, when the animal was restrained and passively rotated through the preferred firing direction. These results indicate that the LDN does not play a substantive role in either the generation or the stability of the HD cell signal in the PoS.

Effects of stimulus sequence on event-related potentials and reaction time during target detection in Alzheimer's disease.

OBJECTIVES: To examine evoked potentials and behavior as a function of stimulus sequence in an auditory target detection paradigm in Alzheimer's disease (AD). METHODS: Evoked potentials and reaction times were collected from 12 healthy elderly controls and 10 patients with mild AD. Subjects pressed a response button to high-pitched target tones (P=0.20) that were randomly intermixed with low-pitched frequent tones. We measured pre-stimulus readiness potential (RP), event-related potentials (P50, N100, P200, N200 and P300), and reaction time as a function of the stimulus sequence. RESULTS: AD subjects performed at comparable levels of accuracy as controls, but had significantly increased reaction times. Grand averaged potentials in AD showed a significant reduction of the amplitude of the RP, and an increase of P300 latency. Both controls and AD showed speeding of reaction time, increases in RP amplitude, and decreases in P300 latency as a function of the number of frequents preceding the target. Sequential changes of other components (P200 and N200) were found in controls but not AD. CONCLUSIONS: AD patients have systematic changes of both RT and certain of the evoked potential components as a function of stimulus sequence. Moment-by-moment changes in target expectancy are largely preserved in AD, even though overall performance and evoked potential measures of expectancy (RP) and stimulus classification (P300 latency) are abnormal.

Age-related qualitative differences in auditory cortical responses during short-term memory.

OBJECTIVE: To examine the affects of aging on auditory cortical activity during a short-term memory task. METHODS: Young and elderly subjects performed a working memory task using acoustically presented digits while evoked potential components (N100, P200) generated by auditory cortex were recorded. Reaction time and N100/P200 amplitudes and latency were analyzed as a function of memory load. RESULTS: N100 amplitude to probes decreased as a function of memory load in young subjects, but increased as a function of memory load in the elderly. Young subjects also exhibited changes in N100 latency during memorization of list items, a result not found in elderly subjects. CONCLUSIONS: We conclude that normal aging is associated with a qualitatively different pattern of N100 responses during memory retrieval, and a static N100 response during encoding. The findings suggest that aging is accompanied by functional reorganization of the neural network that supports retrieval in auditory working memory.

Preparatory slow potentials and event-related potentials in an auditory cued attention task.

OBJECTIVES: To examine reaction times and event-related potentials (ERPs) in an auditory cued attention task varying motor requirements, cue validity, and cue location. METHODS: Subjects (n=13) listened to cue-target stimulus pairs. Verbal cues (monaural, binaural) indicated the ear to receive a target tone 1.5s later. Cues correctly (valid) or incorrectly (invalid) predicted target ear, or were uninformative (neutral). In separate conditions subjects either responded by pressing one of two buttons, or did not respond to targets. ERPs for cues and targets (P50, N100, P200, late slow wave), and negative slow potentials between cues and targets were assessed. RESULTS: Target reaction times for valid cues were significantly shorter than for invalid cues, with intermediate values for neutral cues. When no motor response was required larger ERPs were seen to both cues and targets. Negative slow potentials had larger amplitudes before target presentation when subjects responded to targets; and were larger following neutral, vs. valid/invalid, cues. ERPs (N100, P200) to invalidly cued targets were significantly larger and a subsequent late slow wave was more positive, relative to validly cued targets. CONCLUSIONS: Expectancy for targets begins shortly after cue presentation, and is affected by both motor requirements and the information content of the cue. ERP amplitudes to targets are modulated by the correspondence between cue information and actual target location.

Processing the head direction cell signal: a review and commentary.

Animals require information about their location and directional heading in order to navigate. Directional information is provided by a population of cells in the postsubiculum and the anterior thalamic nuclei that encode a very accurate, continual representation of the animal's directional heading in the horizontal plane, which is independent of the animal's location. Recent studies indicate that this signal 1) arises either in the anterior thalamic nuclei or in structures upstream from it; 2) is not dependent on an intact hippocampus; 3) receives sensory inputs from both idiothetic and landmark systems; and 4) correlates well with the animal's behavior in a spatial reference memory task. Furthermore, HD cells in the anterior thalamic nuclei appear to encode what the animal's directional heading will be about 40 ms in the future, while HD cells in the postsubiculum encode the animal's current directional heading. Both the electrophysiological and anatomical data suggest that the anterior thalamic nuclei and/or the lateral mammillary nuclei may be the sites of convergence for spatial information derived from landmarks and internally-generated cues. Current evidence also indicates that the vestibular system plays a crucial role in the generation of the HD cell signal. However, the notion that the vestibular system is the sole contributor to the signal generator is difficult to reconcile with several findings; these latter findings are better accounted for with a motor efference copy signal.

Cortical event-related potentials in preclinical familial Alzheimer disease.

OBJECTIVE: To define changes in cortical function in persons inheriting familial Alzheimer disease (FAD) mutations before the onset of cognitive decline. METHODS: Twenty-six subjects with a family history of FAD were divided into 2 subgroups according to genotype (FAD mutation carriers, n = 15; FAD noncarriers, n = 11). Subjects were given standardized tests of cognitive function and the Clinical Dementia Rating scale (CDR). Sensory (P50, N100, P200) and cognitive (N200, P300) event-related potentials were recorded during an auditory discrimination task. Amplitudes and latencies of cortical potentials were compared among FAD mutation carriers and noncarriers. RESULTS: FAD mutation carriers and noncarriers did not significantly differ in age or on measures of cognitive function, but FAD carriers had a greater incidence of 0.5 CDR scores (1/10 noncarriers, 5/15 carriers). Relative to noncarriers, FAD mutation carriers had significantly longer latencies of the N100, P200, N200, and P300 components, and smaller slow wave amplitudes. Subanalyses of subjects having CDR scores of 0.0 also showed latency increases in FAD mutation carriers. CONCLUSIONS: Auditory sensory and cognitive cortical potentials in persons with familial Alzheimer disease (FAD) mutations are abnormal approximately 10 years before dementia will be manifest. Longer event-related potential latencies suggest slowing of cortical information processing in FAD mutation carriers.

Head direction cells and episodic spatial information in rats without a hippocampus.

To successfully navigate through the environment animals rely on information concerning their directional heading and location. Many cells within the postsubiculum and anterior thalamus discharge as a function of the animal's head direction (HD), while many cells in the hippocampus discharge in relation to the animal's location. We placed lesions in the hippocampus and recorded from HD cells in the postsubiculum and anterior thalamus. Lesions of the hippocampus did not disrupt the HD cell signal in either brain area, indicating that the HD cell signal must be generated by structures external to the hippocampus. In addition, each cell's preferred firing direction remained stable across days when the lesioned animal was placed into a novel environment. This stability appeared to weaken after several weeks of nonexposure to the new enclosure for two out of five animals, and subsequently recorded cells from these two animals established a new angular relationship between the familiar and novel environments. Our results suggest that extra-hippocampal structures are capable of creating and maintaining a novel representation of the animal's environmental context. This representation shares features in common with mnemonic processes involving episodic memory that until now were assumed to require an intact hippocampus.