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.

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.

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.

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.

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.

Visual motion event related potentials distinguish aging and Alzheimer's disease.

BACKGROUND: Aging and Alzheimer's disease (AD) disrupt visuospatial processing and visual motion evoked potentials in a manner linked to navigational deficits. OBJECTIVE: Our goal is to determine if aging and AD have distinct effects on visual cortical motion processing for navigation. METHODS: We recorded visual motion event related potentials (ERPs) in young (YNC) and older normal controls (ONC), and early AD patients (EADs) who viewed rapidly changing optic flow stimuli that simulate naturalistic changes in heading direction, like those that occur when following a path of self-movement through the environment. After a random series of optic flow stimuli, a vertical motion stimulus was presented to verify sustained visual attention by demanding a rapid push-button response. RESULTS: Optic flow evokes robust ERPs that are delayed in aging and diminished in AD. The interspersed vertical motion stimuli yielded shorter N200 latencies in EADs, matching those in ONCs, but the EADs' N200 amplitudes remained small. CONCLUSIONS: Aging and AD have distinct effects on visual sensory processing: aging delays evoked response, whereas AD diminishes responsiveness.

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.

Independent deficits of visual word and motion processing in aging and early Alzheimer's disease.

We tested whether visual processing impairments in aging and Alzheimer's disease (AD) reflect uniform posterior cortical decline, or independent disorders of visual processing for reading and navigation. Young and older normal controls were compared to early AD patients using psychophysical measures of visual word and motion processing. We find elevated perceptual thresholds for letters and word discrimination from young normal controls, to older normal controls, to early AD patients. Across subject groups, visual motion processing showed a similar pattern of increasing thresholds, with the greatest impact on radial pattern motion perception. Combined analyses show that letter, word, and motion processing impairments are independent of each other. Aging and AD may be accompanied by independent impairments of visual processing for reading and navigation. This suggests separate underlying disorders and highlights the need for comprehensive evaluations to detect early deficits.

Early Alzheimer's disease blocks responses to accelerating self-movement.

We assessed the cortical processing of self-movement stimuli in aging and Alzheimer's disease (AD). Our goal was to identify distinguishing effects on neural mechanisms related to driving and navigation. Young (YNC) and older (ONC) normal controls, and early AD patients (EAD) viewed real-world videos and dot motion stimuli simulating self-movement scenes. We recorded visual motion event related potentials (VMERPs) to stimulus motion coherence and speed. Aging delays motion evoked N200s, whereas AD diminishes response amplitudes. Early Alzheimer's disease patients respond to increments in motion coherence, but they are uniquely unresponsive to increments in motion speed that simulate accelerating self-movement. AD-related impairments of self-movement processing may have grave consequences for driving safety and navigational independence.

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.

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.

Distinct visual motion processing impairments in aging and Alzheimer's disease.

Aging and Alzheimer's disease (AD) are associated with declines in the visual perception of self-movement that undermine navigation and independent living. We studied 214 subjects' heading direction and speed discrimination using the radial patterns of visual motion in optic flow. Young (YA), middle-aged (MA), and older normal (ON) subjects, and AD patients viewed optic flow in which we manipulated the motion coherence, spatial texture, and temporal periodicity composition of the visual display. Aging and AD were associated with poorer heading and speed perception at lower temporal periodicity, with smaller effects of spatial texture. AD patients were particularly impaired by motion incoherence created by adding randomly moving dots to the optic flow. We conclude that visual motion processing is impaired by distinct mechanisms in aging and the transition to AD, implying distinct neural mechanisms of impairment.

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.

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.

Visual motion processing in aging and Alzheimer's disease: neuronal mechanisms and behavior from monkeys to man.

Aging and Alzheimer's disease (AD) are accompanied by impairments of autonomous navigation and spatial orientation that commonly demand the abandonment of driving and independent living. We have studied the neuronal mechanisms of navigation using single neurons in monkey cerebral cortex, finding a specific population of cells that processes the visual motion patterns of optic flow that provide important cues about self-movement. We have found that AD patients show pronounced deficits in the perceptual processing of optic flow, with different patterns of less severe impairment in mild cognitive impairment and cognitive aging. These perceptual deficits occur in subjects who show difficulties in real-world navigation that can be linked to visual associative processing impairments. Human neurophysiological recordings reveal a robust link between navigational capacity and cortical information processing in aging and AD. We conclude that visual information processing is progressively impaired in aging and AD. We speculate that these behavioral impairments reflect the progress of mechanistically linked cortical pathophysiologies that are manifestations of the fateful transition from cognitive aging to AD.