Hyperexcitability in Aging Is Lost in Alzheimer's: What Is All the Excitement About?

Neuronal hyperexcitability has emerged as a potential biomarker of late-onset early-stage Alzheimer's disease (LEAD). We hypothesize that the aging-related posterior cortical hyperexcitability anticipates the loss of excitability with the emergence of impairment in LEAD. To test this hypothesis, we compared the behavioral and neurophysiological responses of young and older (ON) normal adults, and LEAD patients during a visuospatial attentional control task. ONs show frontal cortical signal incoherence and posterior cortical hyper-responsiveness with preserved attentional control. LEADs lose the posterior hyper-responsiveness and fail in the attentional task. Our findings suggest that signal incoherence and cortical hyper-responsiveness in aging may contribute to the development of functional impairment in LEAD.

Path perturbation detection tasks reduce MSTd neuronal self-movement heading responses.

We presented optic flow and real movement heading stimuli while recording MSTd neuronal activity. Monkeys were alternately engaged in three tasks: visual detection of optic flow heading perturbations, vestibular detection of real movement heading perturbations, and auditory detection of brief tones. Push-button RTs were fastest for tones and slower for visual and vestibular heading perturbations, suggesting that the tone detection task was easier. Neuronal heading selectivity was strongest during the tone detection task, and weaker during the visual and vestibular heading perturbation detection tasks. Heading selectivity was weaker during visual and vestibular path perturbation detection, despite our presented heading cues only in the visual and vestibular modalities. We conclude that focusing on the self-movement transients of path perturbation distracted the monkeys from their heading and reduced neuronal responsiveness to heading direction. NEW & NOTEWORTHY Heading analysis is critical for steering and navigation. We recorded the activity of monkey cortical heading neurons during naturalistic self-movement. When the monkeys were required to respond to transient changes in their path, neuronal responses to heading direction were diminished. This suggests that the need to respond to momentary path perturbations reduces your ability to process your heading direction.

Steering Transforms the Cortical Representation of Self-Movement from Direction to Destination.

Steering demands rapid responses to heading deviations and uses optic flow to redirect self-movement toward the intended destination. We trained monkeys in a naturalistic steering paradigm and recorded dorsal medial superior temporal area (MSTd) cortical neuronal responses to the visual motion and spatial location cues in optic flow. We found that neuronal responses to the initial heading direction are dominated by the optic flow's global radial pattern cue. Responses to subsequently imposed heading deviations are dominated by the local direction of motion cue. Finally, as the monkey steers its heading back to the goal location, responses are dominated by the spatial location cue, the screen location of the flow field's center of motion. We conclude that MSTd responses are not rigidly linked to specific stimuli, but rather are transformed by the task relevance of cues that guide performance in learned, naturalistic behaviors. SIGNIFICANCE STATEMENT: Unplanned heading changes trigger lifesaving steering back to a goal. Conventionally, such behaviors are thought of as cortical sensory-motor reflex arcs. We find that a more reciprocal process underlies such cycles of perception and action, rapidly transforming visual processing to suit each stage of the task. When monkeys monitor their simulated self-movement, dorsal medial superior temporal area (MSTd) neurons represent their current heading direction. When monkeys steer to recover from an unplanned change in heading direction, MSTd shifts toward representing the goal location. We hypothesize that this transformation reflects the reweighting of bottom-up visual motion signals and top-down spatial location signals, reshaping MSTd's response properties through task-dependent interactions with adjacent cortical areas.

Navigational path integration by cortical neurons: origins in higher-order direction selectivity.

Navigation relies on the neural processing of sensory cues about observer self-movement and spatial location. Neurons in macaque dorsal medial superior temporal cortex (MSTd) respond to visual and vestibular self-movement cues, potentially contributing to navigation and orientation. We moved monkeys on circular paths around a room while recording the activity of MSTd neurons. MSTd neurons show a variety of sensitivities to the monkey's heading direction, circular path through the room, and place in the room. Changing visual cues alters the relative prevalence of those response properties. Disrupting the continuity of self-movement paths through the environment disrupts path selectivity in a manner linked to the time course of single neuron responses. We hypothesize that sensory cues interact with the spatial and temporal integrative properties of MSTd neurons to derive path selectivity for navigational path integration supporting spatial orientation.

At the interface of sensory and motor dysfunctions and Alzheimer's disease.

Recent evidence indicates that sensory and motor changes may precede the cognitive symptoms of Alzheimer's disease (AD) by several years and may signify increased risk of developing AD. Traditionally, sensory and motor dysfunctions in aging and AD have been studied separately. To ascertain the evidence supporting the relationship between age-related changes in sensory and motor systems and the development of AD and to facilitate communication between several disciplines, the National Institute on Aging held an exploratory workshop titled "Sensory and Motor Dysfunctions in Aging and AD." The scientific sessions of the workshop focused on age-related and neuropathologic changes in the olfactory, visual, auditory, and motor systems, followed by extensive discussion and hypothesis generation related to the possible links among sensory, cognitive, and motor domains in aging and AD. Based on the data presented and discussed at this workshop, it is clear that sensory and motor regions of the central nervous system are affected by AD pathology and that interventions targeting amelioration of sensory-motor deficits in AD may enhance patient function as AD progresses.

Task contingencies and perceptual strategies shape behavioral effects on neuronal response profiles.

We presented optic flow simulating eight directions of self-movement in the ground plane, while monkeys performed delayed match-to-sample tasks, and we recorded dorsal medial superior temporal (MSTd) neuronal activity. Randomly selected sample headings yield smaller test responses to the neuron's preferred heading when it is near the sample's heading direction and larger test responses to the preferred heading when it is far from the sample's heading. Limiting test stimuli to matching or opposite headings suppresses responses to preferred stimuli in both test conditions, whereas focusing on each neuron's preferred vs. antipreferred stimuli enhances responses to the antipreferred stimulus. Match vs. opposite paradigms create bimodal heading profiles shaped by interactions with late delay-period activity. We conclude that task contingencies, determining the prior probabilities of specific stimuli, interact with the monkeys' perceptual strategy for optic flow analysis. These influences shape attentional and working memory effects on the heading direction selectivities and preferences of MSTd neurons.

Driving strategy alters neuronal responses to self-movement: cortical mechanisms of distracted driving.

We presented naturalistic combinations of virtual self-movement stimuli while recording neuronal activity in monkey cerebral cortex. Monkeys used a joystick to drive to a straight ahead heading direction guided by either object motion or optic flow. The selected cue dominates neuronal responses, often mimicking responses evoked when that stimulus is presented alone. In some neurons, driving strategy creates selective response additivities. In others, it creates vulnerabilities to the disruptive effects of independently moving objects. Such cue interactions may be related to the disruptive effects of independently moving objects in Alzheimer's disease patients with navigational deficits.

Neural activity during monkey vehicular wayfinding.

Navigation gets us from place to place, creating a path to arrive at a goal. We trained a monkey to steer a motorized cart in a large room, beginning at its trial-by-trial start location and ending at a trial-by-trial cued goal location. While the monkey steered its autonomously chosen path to its goal, we recorded neural activity simultaneously in both the hippocampus (HPC) and medial superior temporal (MST) cortex. Local field potentials (LFPs) in these sites show similar patterns of activity with the 15-30 Hz band highlighting specific room locations. In contrast, 30-100 Hz LFPs support a unified map of the behaviorally relevant start and goal locations. The single neuron responses (SNRs) do not substantially contribute to room or start-goal maps. Rather, the SNRs form a continuum from neurons that are most active when the monkey is moving on a path toward the goal, versus other neurons that are most active when the monkey deviates from paths toward the goal. Granger analyses suggest that HPC firing precedes MST firing during cueing at the trial start location, mainly mediated by off-path neurons. In contrast, MST precedes HPC firing during steering, mainly mediated by on-path neurons. Interactions between MST and HPC are mediated by the parallel activation of on-path and off-path neurons, selectively activated across stages of this wayfinding task.

Harnessing neuroplasticity for clinical applications.

Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.

Approaching objects cause confusion in patients with Alzheimer's disease regarding their direction of self-movement.

Navigation requires real-time heading estimation based-on self-movement cues from optic flow and object motion. We presented a simulated heading discrimination task to young, middle-aged and older adult, normal, control subjects and to patients with mild cognitive impairment or Alzheimer's disease. Age-related decline and neurodegenerative disease effects were evident on a battery of neuropsychological and visual motion psychophysical measures. All subject groups made more accurate heading judgements when using optic flow patterns than when using simulated movement past earth-fixed objects. When both optic flow and congruent object were presented together, heading judgements showed intermediate accuracy. In separate trials, we combined optic flow with non-congruent object motion, simulating an independently moving object. In the case of non-congruent objects, almost all of our subjects shifted their perceived self-movement to heading in the direction of the moving object. However, patients with Alzheimer's disease uniquely indicated that perceived self-movement was straight-ahead, in the direction of visual fixation. The tendency to be confused by objects that appear to move independently in the simulated visual scene corresponded to the difficulty patients with Alzheimer's disease encountered in real-world navigation through the hospital lobby (R(2) = 0.87). This was not the case in older normal controls (R(2) = 0.09). We conclude that perceptual factors limit safe, autonomous navigation in early Alzheimer's disease. In particular, the presence of independently moving objects in naturalistic environments limits the capacity of patients with Alzheimer's disease to judge their heading of self-movement.

Receptive field dynamics underlying MST neuronal optic flow selectivity.

Optic flow informs moving observers about their heading direction. Neurons in monkey medial superior temporal (MST) cortex show heading selective responses to optic flow and planar direction selective responses to patches of local motion. We recorded MST neuronal responses to a 90 x 90 degrees optic flow display and to a 3 x 3 array of local motion patches covering the same area. Our goal was to test the hypothesis that the optic flow responses reflect the sum of the local motion responses. The local motion responses of each neuron were modeled as mixtures of Gaussians, combining the effects of two Gaussian response functions derived using a genetic algorithm, and then used to predict that neuron's optic flow responses. Some neurons showed good correspondence between local motion models and optic flow responses, others showed substantial differences. We used the genetic algorithm to modulate the relative strength of each local motion segment's responses to accommodate interactions between segments that might modulate their relative efficacy during co-activation by global patterns of optic flow. These gain modulated models showed uniformly better fits to the optic flow responses, suggesting that coactivation of receptive field segments alters neuronal response properties. We tested this hypothesis by simultaneously presenting local motion stimuli at two different sites. These two-segment stimuli revealed that interactions between response segments have direction and location specific effects that can account for aspects of optic flow selectivity. We conclude that MST's optic flow selectivity reflects dynamic interactions between spatially distributed local planar motion response mechanisms.

Cortical neurons combine visual cues about self-movement.

Visual cues about self-movement are derived from the patterns of optic flow and the relative motion of discrete objects. We recorded dorsal medial superior temporal (MSTd) cortical neurons in monkeys that held centered visual fixation while viewing optic flow and object motion stimuli simulating the self-movement cues seen during translation on a circular path. Twenty stimulus configurations presented naturalistic combinations of optic flow with superimposed objects that simulated either earth-fixed landmark objects or independently moving animate objects. Landmarks and animate objects yield the same response interactions with optic flow; mainly additive effects, with a substantial number of sub- and super-additive responses. Sub- and super-additive interactions reflect each neuron's local and global motion sensitivities: Local motion sensitivity is based on the spatial arrangement of directions created by object motion and the surrounding optic flow. Global motion sensitivity is based on the temporal sequence of self-movement headings that define a simulated path through the environment. We conclude that MST neurons' spatio-temporal response properties combine object motion and optic flow cues to represent self-movement in diverse, naturalistic circumstances.

Distinct mechanisms of impairment in cognitive ageing and Alzheimer's disease.

Similar manifestations of functional decline in ageing and Alzheimer's disease obscure differences in the underlying cognitive mechanisms of impairment. We sought to examine the contributions of top-down attentional and bottom-up perceptual factors to visual self-movement processing in ageing and Alzheimer's disease. We administered a novel heading discrimination task requiring subjects to determine direction of simulated self-movement from left or right offset optic flow fields of several sizes (25 degrees, 40 degrees or 60 degrees in diameter) to 18 Alzheimer's disease subjects (mean age = 75.3, 55% female), 21 older adult control subjects (mean age = 72.4, 67% female), and 26 younger control subjects (mean age = 26.5, 63% female). We also administered computerized measures of processing speed and divided and selective attention, and psychophysical measures of visual motion perception to all subjects. Both older groups showed significant difficulty in judging the direction of virtual self-movement [F(2,194) = 40.5, P < 0.001] and optic flow stimulus size had little effect on heading discrimination for any group. Both older groups showed impairments on measures of divided [F(2,62) = 22.2, P < 0.01] and selective [F(2,62) = 63.0, P < 0.001] attention relative to the younger adult control group, while the Alzheimer's disease group showed a selective impairment in outward optic flow perception [F(2,64) = 6.3, P = 0.003] relative to both control groups. Multiple linear regression revealed distinct attentional and perceptual contributions to heading discrimination performance for the two older groups. In older adult control subjects, poorer heading discrimination was attributable to attentional deficits (R(2) adj = 0.41, P = 0.001) whereas, in Alzheimer's disease patients, it was largely attributable to deficits of visual motion perception (R(2) adj = 0.57, P < 0.001). These findings suggest that successive attentional and perceptual deficits play independent roles in the progressive functional impairments of ageing and Alzheimer's disease. We speculate that the attentional deficits that dominate in older adults may promote the development of the perceptual deficits that further constrain performance in Alzheimer's disease.

Cortical neuronal responses to optic flow are shaped by visual strategies for steering.

We hypothesized that neuronal responses to virtual self-movement would be enhanced during steering tasks. We recorded the activity of medial superior temporal (MSTd) neurons in monkeys trained to steer a straight-ahead course, using optic flow. We found smaller optic flow responses during active steering than during the passive viewing of the same stimuli. Behavioral analysis showed that the monkeys had learned to steer using local motion cues. Retraining the monkeys to use the global pattern of optic flow reversed the effects of the active-steering task: active steering then evoked larger responses than passive viewing. We then compared the responses of neurons during active steering by local motion and by global patterns: Local motion trials promoted the use of local dot movement near the center of the stimulus by occluding the peripheral visual field midway through the trial. Global pattern trials promoted the use of radial pattern movement by occluding the central visual field midway through the trial. In this study, identical full-field optic-flow stimuli evoked larger responses in global-pattern trials than in local motion trials. We conclude that the selection of specific visual cues reflects strategies for active steering and alters MSTd neuronal responses to optic flow.

White matter integrity linked to functional impairments in aging and early Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is associated with changes in cerebral white matter (WM), but the functional significance of such findings is not yet established. We hypothesized that diffusion tensor imaging (DTI) might reveal links between regional WM changes and specific neuropsychologically and psychophysically defined impairments in early AD. METHODS: Older adult control subjects (OA, n = 18) and mildly impaired AD patients (n = 14) underwent neuropsychological and visual perceptual testing along with DTI of cerebral WM. DTI yielded factional anisotropy (FA) and mean diffusivity (D) maps for nine regions of interest in three brain regions that were then compared with the performance measures. RESULTS: AD patients exhibited nonsignificant trends toward lower FAs in the posterior region's callosal and subcortical regions of interest. However, posterior callosal FA was significantly correlated with verbal fluency and figural memory impairments, whereas posterior subcortical FA was correlated with delayed verbal memory, figural memory, and optic flow perceptual impairments. CONCLUSIONS: WM changes in early AD are concentrated in posterior cerebral areas, with distributions that correspond to specific functional impairments. DTI can be used to assess regional pathology related to individual's deficits in early AD.

Attentional ERPs distinguish aging and early Alzheimer's dementia.

The early detection of Alzheimer's disease requires our distinguishing it from cognitive aging. Here, we test whether spatial attentional changes might support that distinction. We engaged young normal (YN), older normal (ON), and patients with early Alzheimer's dementia (EAD) in an attentionally cued, self-movement heading discrimination task while we recorded push-button response times and event related potentials. YNs and ONs show the behavioral effects of attentional shifts from the cue to the target, whereas EAD patients did not (p < 0.001). YNs and ONs also show the shifting lateralization of a newly described attentional event related potentials component, whereas EAD patients did not (p < 0.001). Our findings suggest that spatial inattention in EAD patients may contribute to heading direction processing impairments that distinguish them from ONs and undermine their navigational capacity and driving safety.

Cue integration for the perception and control of self-movement in ageing and Alzheimer's disease.

The perception and control of self-movement relies on visual cues derived from the radial patterns of optic flow and from the relative motion of objects within view. Optic flow and object motion processing impairments might limit independent self-movement in a manner like that seen in ageing and in Alzheimer's disease. We used optic flow and object motion stimuli to simulate aspects of the self-movement scene. Stimulus salience was individualized to present comparable stimuli to young [n = 18; mean age = 25.6, standard error of measurement (SEM) = 1.4], middle-aged (n = 17; mean age = 53.9, SEM = 0.9), older adult (n = 30; mean age = 72.4, SEM = 1.4) and Alzheimer's disease (n = 15; mean age 75.2, SEM = 1.6) subjects. All groups were tested in two tasks: pointing towards the simulated direction of self-movement and steering the simulated self-movement towards a straight-ahead direction. We found that young and middle-aged subjects show similar pointing accuracy using either optic flow or object motion, but steer better with object motion than with optic flow. Older adult subjects show better performance with optic flow than object cues for pointing (P < 0.001), but their performance improves when both cues are combined in the pointing (P = 0.012) and steering (P = 0.02) tasks. Alzheimer's disease patients show poorer performance with optic flow and object motion than all other groups and do not benefit from the combined presentation of cues for either pointing or steering. We conclude that ageing and Alzheimer's disease are associated with distinct profiles of visual processing deficits that limit the ability to use optic flow and object motion to perceive and control self-movement.

Neurophysiological and perceptual correlates of navigational impairment in Alzheimer's disease.

We assessed visual processing related to navigational impairment in Alzheimer's disease hypothesizing that visual motion evoked responses to optic flow simulating observer self-movement would be linked to navigational performance. Mild Alzheimer's disease and older adult control subjects underwent open-field navigational testing, visual motion perceptual threshold determination and a battery of neuropsychological examinations. We recorded visual motion evoked potentials (EPs) at occipital and parietal sites during centred visual fixation. Randomly moving or stationary pattern pre-stimuli preceded horizontal motion and radial optic flow stimuli to separate motion N200s from pattern onset responses. Radial optic flow evoked N200 responses comparable with those obtained with uniform horizontal motion, despite the variety of motion directions in radial optic flow. Alzheimer's disease patients showed smaller radial optic flow N200s than older adult subjects, and these were greatly diminished when preceded by stationary dots. Combining N200 amplitudes with optic flow perceptual thresholds and contrast sensitivities yielded a strong correlation with navigational impairment in Alzheimer's disease (R2 = 0.95). We conclude that navigational impairment in Alzheimer's disease is linked to a disorder of extrastriate visual cortical motion processing reflected in specific perceptual and neurophysiological measures.

Pursuit neurons encode 3D space: is the cortex nervous and tensor?

Fukushima and colleagues have found single neurons in monkey frontal cortex that control pursuit eye movements by representing extra-personal space in a 3D-coordinate frame. These cells might link the 2D depiction of visual space by the retina with the need of the body to act in the 3D world. We could be on the verge of a new understanding of coordinate transformations serving sensory-motor integration in cerebral cortex.

Might cortical hyper-responsiveness in aging contribute to Alzheimer's disease?

Our goal is to understand the neural basis of functional impairment in aging and Alzheimer's disease (AD) to be able to characterize clinically significant decline and assess therapeutic efficacy. We used frequency-tagged ERPs to word and motion stimuli to study the effects of stimulus conditions and selective attention. ERPs to word or motion increase when a task-irrelevant 2nd stimulus is added, but decrease when the task is moved to that 2nd stimulus. Spectral analyses show task effects on response power without 2nd stimulus effects. However, phase coherence shows both 2nd stimulus and task effects. Thus, power and coherence are dissociably modulated by stimulus and task effects. Task-dependent phase coherence successively declines in aging and AD. In contrast, task-dependent spectral power increases in aging, only to decrease in AD. We hypothesize that age-related declines in signal coherence, associated with increased power generation, stresses neurons and contributes to the loss of response power and the development of functional impairment in AD.