Charles J. Duffy

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.

Detecting navigational deficits in cognitive aging and Alzheimer disease using virtual reality.

Background: Older adults get lost, in many cases because of recognized or incipient Alzheimer disease (AD). In either case, getting lost can be a threat to individual and public safety, as well as to personal autonomy and quality of life. Here we compare our previously described real-world navigation test with a virtual reality (VR) version simulating the same navigational environment. Methods: Quantifying real-world navigational performance is difficult and time-consuming. VR testing is a promising alternative, but it has not been compared with closely corresponding real-world testing in aging and AD. We have studied navigation using both real-world and virtual environments in the same subjects: young normal controls (YNCs, n = 35), older normal controls (ONCs, n = 26), patients with mild cognitive impairment (MCI, n = 12), and patients with early AD (EAD, n = 14). Results: We found close correlations between real-world and virtual navigational deficits that increased across groups from YNC to ONC, to MCI, and to EAD. Analyses of subtest performance showed similar profiles of impairment in real-world and virtual testing in all four subject groups. The ONC, MCI, and EAD subjects all showed greatest difficulty in self-orientation and scene localization tests. MCI and EAD patients also showed impaired verbal recall about both test environments. Conclusions: Virtual environment testing provides a valid assessment of navigational skills. Aging and Alzheimer disease (AD) share the same patterns of difficulty in associating visual scenes and locations, which is complicated in AD by the accompanying loss of verbally mediated navigational capacities. We conclude that virtual navigation testing reveals deficits in aging and AD that are associated with potentially grave risks to our patients and the community.

Spatial disorientation in Alzheimer’s disease The remembrance of things passed

Background: Patients with Alzheimer’s disease (AD) and many older adults become lost even in familiar surroundings. This is commonly attributed to memory impairment, but it may reflect impaired spatial cognition. Methods: The authors examined the role of memory, perceptual, and cognitive mechanisms in spatial disorientation by comparing the performance of normal young (YN), middle-aged (MA), older adult (OA), and AD subjects on neuropsychological and spatial orientation tests. Results: The tendency to become lost is shared by almost all patients with AD (93%) and some OA subjects (38%). This impairment is not related to memory impairment. Instead, it reflects an inability to link recognized scenes with locations in the environment. Conclusions: Spatial disorientation reflects the impaired linking of landmarks and routes that should be assessed in conjunction with routine memory testing in elderly patients.

A visuospatial variant of mild cognitive impairment: getting lost between aging and AD.

Background: AD causes visuospatial disorientation that is associated with posterior cortical atrophy and impaired visual motion processing. Objective: The authors characterized memory capacity and visual motion processing in young normal (YN) and older normal (ON) adult subjects and in patients with mild cognitive impairment (MCI) and AD to see if deficits in these realms occur as isolated impairments. Methods: Each participant underwent neuropsychological testing and gave push-button responses to indicate perception of panoramic visual motion stimuli. Results: One fifth of the ON subjects, one third of the patients with MCI, and half of the patients with AD showed increasingly pervasive impairments of visual motion perception. These impairments were associated with poorer performance on the Money Road Map test of spatial navigation but not with verbal or visual memory deficits. Conclusion: Impaired visual motion processing may accompany memory deficits in MCI or AD, or may occur alone in otherwise intact ON subjects. This suggests that visuospatial impairment may develop as an independent sign of neurodegenerative disease, possibly preceding the clinical onset of AD.

Visual loss and getting lost in Alzheimer's disease

Background: AD causes patients to get lost in familiar surroundings, in part because of visuospatial disorientation from parieto-occipital involvement. Parieto-occipital cortex analyzes the radial patterns of visual motion that create optic flow and guide movements through the environment by showing one’s direction of self-movement. Objective: To determine whether AD patients are impaired in perceiving the visual patterns of optic flow, suggesting a perceptual mechanism of visuospatial disorientation. Methods: We studied the ability of young normal subjects, elderly normal subjects, and AD patients to see and interpret visual patterns, including the radial motion of optic flow. Each person sat in front of a panoramic computer display and gave push-button responses to indicate their perception of the projected visual stimuli. Spatial navigation was tested by asking questions about a recently traversed path. Results: Half of the AD subjects showed impaired optic flow perception that was associated with poor performance on the spatial navigation test, even though their perception of simple moving patterns was relatively preserved. Some AD subjects also showed a separate impairment in interpreting optic flow, so that they could not use those stimuli to judge their direction of self-movement. Conclusions: AD greatly impairs the ability to see the radial patterns of optic flow. This may interfere with the use of visual information to guide self-movement and maintain 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 Alzheimers 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.

An illusory transformation of optic flow fields

We compared a human observers ability to locate the focus of expansion (FOE) of a radial optic flow field when this flow field was either combined with, or overlapped by, planar motion. With combined stimuli, in which the FOE was displaced in the direction opposite to the planar motion, subjects accurately located the displaced FOE. With overlapping (transparent) stimuli and the FOE remaining in the center of the display, we found an illusory transformation of the radial pattern: the focus of expansion appeared to be shifted in the direction of the planar motion. The speed of both the planar and radial patterns of motion influenced the illusion. Presence or absence of visual fixation had little effect. We suggest that this illusion might provide a clue as to the way the brain processes planar and radial motion which might in turn be relevant to the interaction of the planar and radial motion components of optic flow fields.

Neurophysiologic analyses of low- and high-level visual processing in Alzheimer disease

Objective: We developed visual motion evoked potential (EP) measures related to navigational impairment in Alzheimer disease (AD) and have now applied these methods to explore the role of elementary perceptual and attentional mechanisms mediating these effects. Methods: Older adult (OA) control subjects and AD patients underwent visual motion perceptual testing, attentional performance monitoring, and basic neuropsychological and visual assessments. We recorded stationary pattern onset and visual motion onset EPs as well as behavioral event–related potentials during centered visual fixation. Results: Psychophysical assessment demonstrated visual motion perceptual impairments in patients with AD, half of whom also showed low sensitivity in the attentional task. The low sensitivity AD patients had small pattern onset and absent motion onset EPs, whereas the high sensitivity AD patients had large pattern onset EPs and normal motion onset EPs. Conclusions: We conclude that visual evoked potentials (EPs) are abnormal in all patients with Alzheimer disease (AD): Those with small pattern and motion onset EPs may have greater AD pathology in visual cortex, whereas those with larger pattern onset EPs may have greater AD pathology in higher centers. These findings highlight the utility of visual EPs in distinguishing between syndromic variants of AD associated with particular patterns of functional decline.

Neuronal Correlates of Optic Flow Stimulation

Neurons in a region of monkey extrastriate cortex, MSTd, respond to the components of optic flow stimulation. Some of these neurons (single-component neurons) are selective for a single type of motion such as inward- or outward-radial motion. Other neurons respond to multiple types of rotation, for example, rightward planar, clockwise circular, and inward radial. Rather than forming discrete groups, we think these neurons represent a continuum covering the range from single-component sensitivity to multiple-component sensitivity. By combining the optic flow stimuli, we have also been able to recognize that such combinations alter the response of cells in the continuum to varying degrees. At this point, while our evidence is consistent with the hypothesis that cells in area MSTd contribute to the processing of optic flow stimuli, we do not know whether these neurons do in fact serve this function. As in all single-cell recording experiments, even those in awake animals performing tasks closer to real-world tasks than we have succeeded in emulating here, the activity of the cell in relationship to the visual stimulation is simply a correlate of the optic flow stimulation and may or may not contribute to the processing of optic flow stimulation upon which behavior depends. Further information on a number of characteristics of these cells might clarify their role. Information on such factors as whether heading in the environment is conveyed by individual neurons, or whether this property is more likely to be conveyed over a population of neurons, and the role of changes in the point of fixation of the eyes are critical points. Generation of behavior on the basis of the optic flow stimulation and determination that this behavior is modified by selective lesion of MSTd would also strengthen the argument that visual motion processing in this area is related to analyzing optic flow information.

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

Similar manifestations of functional decline in ageing and Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers 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 Alzheimers disease.