Normalization of neuronal responses in cortical area MT across signal strengths and motion directions.

Multiple visual stimuli are common in natural scenes, yet it remains unclear how multiple stimuli interact to influence neuronal responses. We investigated this question by manipulating relative signal strengths of two stimuli moving simultaneously within the receptive fields (RFs) of neurons in the extrastriate middle temporal (MT) cortex. Visual stimuli were overlapping random-dot patterns moving in two directions separated by 90°. We first varied the motion coherence of each random-dot pattern and characterized, across the direction tuning curve, the relationship between neuronal responses elicited by bidirectional stimuli and by the constituent motion components. The tuning curve for bidirectional stimuli showed response normalization and can be accounted for by a weighted sum of the responses to the motion components. Allowing nonlinear, multiplicative interaction between the two component responses significantly improved the data fit for some neurons, and the interaction mainly had a suppressive effect on the neuronal response. The weighting of the component responses was not fixed but dependent on relative signal strengths. When two stimulus components moved at different coherence levels, the response weight for the higher-coherence component was significantly greater than that for the lower-coherence component. We also varied relative luminance levels of two coherently moving stimuli and found that MT response weight for the higher-luminance component was also greater. These results suggest that competition between multiple stimuli within a neuron's RF depends on relative signal strengths of the stimuli and that multiplicative nonlinearity may play an important role in shaping the response tuning for multiple stimuli.

Phenotypes of hypofrontality in older female fragile X premutation carriers.

OBJECTIVE: To investigate the nature of cognitive impairments and underlying brain mechanisms in older female fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome (FXTAS). METHODS: Extensive neuropsychological testing and cognitive event-related brain potentials (ERPs; particularly, the auditory P300) were examined in 84 female participants: 33 fragile X premutation carriers with FXTAS (mean age = 62.8 years), 25 premutation carriers without FXTAS (mean age = 55.4 years), and 26 normal healthy controls (mean age = 59.3 years). RESULTS: Both premutation groups exhibited executive dysfunction on the Behavioral Dyscontrol Scale, with subtle impairments in inhibition and performance monitoring in female carriers without FXTAS, and more substantial deficits in FXTAS women. However, the female carrier group without FXTAS showed more pronounced deficiencies in working memory. Abnormal ERPs were recorded over the frontal lobes, where FXTAS patients showed both P300 amplitude reduction and latency prolongation, whereas only decreased frontal P300 amplitudes were found in carriers without FXTAS. These frontal P300 measures correlated with executive function and information processing speed. INTERPRETATION: The neuropsychological testing and ERP results of the present study provide support for the hypothesis that executive dysfunction is the primary cognitive impairment among older female premutation carriers both with and without FXTAS, although these deficits are relatively mild compared to those in FXTAS males. These findings are consistent with a synergistic effect of the premutation and aging on cognitive impairment among older female fragile X premutation carriers, even in those without FXTAS symptoms.

Neural substrates of executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS): a brain potential study.

Executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS) has been suggested to mediate other cognitive impairments. In the present study, event-related potentials and neuropsychological testing were combined to investigate the brain mechanisms underlying the executive dysfunction in FXTAS. Thirty-two-channel electroencephalography was recorded during an auditory "oddball" task requiring dual responses. FXTAS patients (N= 41, mean age= 62) displayed prolonged latencies of N1 and P3 and reduced amplitudes of P2 and P3, whereas their N2 measures remained within the normal range, indicating relatively preserved early-stage auditory attention but markedly impaired late-stage attention and working memory updating processes (as indexed by P3). Topographical mapping revealed a typical parietal P3 peak preceded by a prominent fronto-central P3 in normal control subjects (N= 32), whereas FXTAS patients had decreased parietal P3 amplitude and diminished fronto-central positivities with a delayed onset (∼50 ms later than controls, P < 0.002). The P3 abnormalities were associated with lower executive function test (e.g., BDS-2) scores. Smaller P3 amplitudes also correlated with increased CGG repeat length of fragile X mental retardation 1 (FMR1) gene and higher FMR1 mRNA levels. These results indicate that abnormal fronto-parietal attentional network dynamics underlie executive dysfunction, the cardinal feature of cognitive impairment in FXTAS.

Sensory versus motor loci for integration of multiple motion signals in smooth pursuit eye movements and human motion perception.

We have investigated how visual motion signals are integrated for smooth pursuit eye movements by measuring the initiation of pursuit in monkeys for pairs of moving stimuli of the same or differing luminance. The initiation of pursuit for pairs of stimuli of the same luminance could be accounted for as a vector average of the responses to the two stimuli singly. When stimuli comprised two superimposed patches of moving dot textures, the brighter stimulus suppressed the inputs from the dimmer stimulus, so that the initiation of pursuit became winner-take-all when the luminance ratio of the two stimuli was 8 or greater. The dominance of the brighter stimulus could be not attributed to either the latency difference or the ratio of the eye accelerations for the bright and dim stimuli presented singly. When stimuli comprised either spot targets or two patches of dots moving across separate locations in the visual field, the brighter stimulus had a much weaker suppressive influence; the initiation of pursuit could be accounted for by nearly equal vector averaging of the responses to the two stimuli singly. The suppressive effects of the brighter stimulus also appeared in human perceptual judgments, but again only for superimposed stimuli. We conclude that one locus of the interaction of two moving visual stimuli is shared by perception and action and resides in local inhibitory connections in the visual cortex. A second locus resides deeper in sensory-motor processing and may be more closely related to action selection than to stimulus selection.

Thalamic neurons in the pigeon compute distance-to-collision of an approaching surface.

The thalamofugal and tectofugal pathways in birds are two parallel visual pathways to the telencephalon and might be comparable to the geniculocortical and colliculo-pulvinar-cortical pathways in mammals, respectively. It is known that some tectal neurons in the tectofugal pathway can signal the time-to-collision of an approaching object. Here we show by single cell recording in the pigeon that a population of visual neurons in the nucleus opticus principalis thalami (nOPT) in the thalamofugal pathway is able to detect the distance-to-collision of a large surface approaching towards the animal. These neurons began response firing when the surface reached a threshold distance to the viewing eye and thereafter their firing rates increased exponentially until collision occurred at distance = zero. The response onset distance is nearly constant for a wide range of stimulus velocities and is equal to the product of velocity of approaching stimulus and response onset time of a nOPT cell. Furthermore, onset distance of looming responses in nOPT cells is close to that causing cardioacceleration in the pigeon viewing the approaching surface. It appears that nOPT and tectal neurons are dichotomized functionally to a large extent for detecting imminent dangers, and the pigeon's ability to compute the distance-to-collision of an approaching surface may benefit avoiding large obstacles during flight.

EEG oscillations during word processing predict MCI conversion to Alzheimer's disease.

Only a subset of mild cognitive impairment (MCI) patients progress to develop a form of dementia. A prominent feature of Alzheimer's disease (AD) is a progressive decline in language. We investigated if subtle anomalies in EEG activity of MCI patients during a word comprehension task could provide insight into the likelihood of conversion to AD. We studied 25 amnestic MCI patients, a subset of whom developed AD within 3-years, and 11 elderly controls. In the task, auditory category descriptions (e.g., 'a type of wood') were followed by a single visual target word either semantically congruent (i.e., oak) or incongruent with the preceding category. We found that the MCI convertors group (i.e. patients that would go on to convert to AD in 3-years) had a diminished early posterior-parietal theta (3-5 Hz) activity induced by first presentation of the target word (i.e., access to lexico-syntactic properties of the word), compared to MCI non-convertors and controls. Moreover, MCI convertors exhibited oscillatory signatures for processing the semantically congruent words that were different from non-convertors and controls. MCI convertors thus showed basic anomalies for lexical and meaning processing. In addition, both MCI groups showed anomalous oscillatory signatures for the verbal learning/memory of repeated words: later alpha suppression (9-11 Hz), which followed first presentation of the target word, was attenuated for the second and third repetition in controls, but not in either MCI group. Our findings suggest that a subtle breakdown in the brain network subserving language comprehension can be foretelling of conversion to AD.

Cognitive Deficits and Associated ERP N400 Abnormalities in FXTAS With Parkinsonism.

Objective: To examine cognitive deficits and associated brain activity in fragile X-associated tremor/ataxia syndrome (FXTAS) patients with parkinsonism (FXTp+), in relation to FXTAS patients without parkinsonism (FXTp-), and normal elderly controls (NC). Methods: Retrospective reviews were performed in 65 FXTAS patients who participated in the event-related brain potential (ERP) study and also had either a videotaped neurological examination or a neurological examination for extrapyramidal signs. Parkinsonism was defined as having bradykinesia with at least one of the following: rest tremor, postural instability, hypermyotonia, or rigidity. Eleven FXTp+ patients were identified and compared to 11 matched FXTp- and 11 NC. Main ERP measures included the N400 congruity effect, N400 repetition effect, and the late positive component (LPC) repetition effect. Results: When compared with FXTp- and NC, the FXTp+ group showed more severe deficits in executive function, cued-recall, recognition memory, along with a significantly reduced N400 repetition effect (thought to index semantic processing and verbal learning/memory) which was correlated with poorer verbal memory. Across all patients, FMR1 mRNA levels were inversely correlated with delayed recall on the California Verbal Learning Test (CVLT). Interpretation: The findings of more prominent executive dysfunction and verbal learning/memory deficits in FXTp+ than FXTp- are consistent with findings in Parkinson's disease (PD), and may indicate that concomitant and/or synergistic pathogenetic mechanisms associated with PD play a role in FXTAS. These results have implications not only for understanding the cognitive impairments associated with the parkinsonism subtype of FXTAS, but also for the development of new interventions for these patients.

Memantine Improves Attentional Processes in Fragile X-Associated Tremor/Ataxia Syndrome: Electrophysiological Evidence from a Randomized Controlled Trial.

Progressive cognitive deficits are common in patients with fragile X-associated tremor/ataxia syndrome (FXTAS), with no targeted treatment yet established. In this substudy of the first randomized controlled trial for FXTAS, we examined the effects of NMDA antagonist memantine on attention and working memory. Data were analyzed for patients (24 in each arm) who completed both the primary memantine trial and two EEG recordings (at baseline and follow-up) using an auditory "oddball" task. Results demonstrated significantly improved attention/working memory performance after one year only for the memantine group. The event-related potential P2 amplitude elicited by non-targets was significantly enhanced in the treated group, indicating memantine-associated improvement in attentional processes at the stimulus identification/discrimination level. P2 amplitude increase was positively correlated with improvement on the behavioral measure of attention/working memory during target detection. Analysis also revealed that memantine treatment normalized the P2 habituation effect at the follow-up visit. These findings indicate that memantine may benefit attentional processes that represent fundamental components of executive function/dysfunction, thought to comprise the core cognitive deficit in FXTAS. The results provide evidence of target engagement of memantine, as well as therapeutically relevant information that could further the development of specific cognitive or disease-modifying therapies for FXTAS.

Parkinsonism in fragile X-associated tremor/ataxia syndrome (FXTAS): revisited.

BACKGROUND: Parkinsonian features have been used as a minor diagnostic criterion for fragile X-associated tremor/ataxia syndrome (FXTAS). However, prior studies have examined parkinsonism (defined as having bradykinesia with at least rest tremor or postural instability) mostly in premutation carriers without a diagnosis of FXTAS. The current study was intended to elaborate this important aspect of the FXTAS spectrum, and to quantify the relationships between parkinsonism, FXTAS clinical staging and genetic/molecular measures. METHODS: Thirty eight (38) FXTAS patients and 10 age-matched normal controls underwent a detailed neurological examination that included all but one item (i.e. rigidity) of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: The FXTAS patient group displayed substantially higher prevalence of parkinsonian features including body bradykinesia (57%) and rest tremor (26%), compared to the control group. Furthermore, parkinsonism was identified in 29% of FXTAS patients. Across all patients, body bradykinesia scores significantly correlated with FXTAS clinical stage, FMR1 mRNA level, and ataxic gait of cerebellar origin, while postural instability was associated with intention tremor. INTERPRETATION: Parkinsonian features in FXTAS appear to be characterized as bradykinesia concurrent with cerebellar gait ataxia, postural instability accompanied by intention tremor, and frequent rest tremor, representing distinctive patterns that highlight the need for further clinical studies including genetic testing for the FMR1 premutation. The association between FMR1 mRNA level and bradykinesia implicates pathophysiological mechanisms which may link FMR1 mRNA toxicity, dopamine deficiency and parkinsonism in FXTAS.

Memantine effects on verbal memory in fragile X-associated tremor/ataxia syndrome (FXTAS): a double-blind brain potential study.

Older FMR1 premutation carriers may develop fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder manifesting cognitive deficits that often subsequently progress to dementia. To date, there is no specific treatment available for FXTAS. Studies have demonstrated the premutation-associated overactivation of glutamatergic receptors in neurons. Memantine, a NMDA receptor antagonist approved for treatment of Alzheimer's disease, thus was tested in the first placebo-controlled, double-blind, randomized clinical trial in FXTAS. Prior event-related brain potential (ERP) studies in FXTAS found reduced N400 repetition effect, a glutamate-related electrophysiological marker of semantic priming, and verbal memory processes. This substudy of the randomized clinical trial of memantine in FXTAS sought to use the N400 repetition effect to evaluate effects of chronic memantine treatment on verbal memory. Subsequent recall and recognition memory tests for the experimental stimuli were administered to characterize verbal memory. Data from 41 patients who completed the 1-year memantine trial (21 on memantine) and also completed longitudinal ERP studies were analyzed. Results showed treatment-associated benefits on both cued-recall memory and N400 repetition effect amplitude. Importantly, improvement in cued recall was positively correlated with amplitude increase of the N400 repetition effect. The placebo group, in contrast, displayed a significant reduction of the N400 repetition effect after 1 year. These results suggest that memantine treatment may have beneficial effects on verbal memory in FXTAS. Additional studies of memantine, perhaps in combination with other therapeutic agents, appear warranted, as symptomatic treatments and neuroprotective treatments are both needed for this recently recognized neurodegenerative disorder.

Response characteristics of the pigeon's pretectal neurons to illusory contours and motion.

Misinterpretations of visual information received by the retina are called visual illusions, which are known to occur in higher brain areas. However, whether they would be also processed in lower brain structures remains unknown, and how to explain the neuronal mechanisms underlying the motion after-effect is intensely debated. We show by extracellular recording that all motion-sensitive neurons in the pigeon's pretectum respond similarly to real and illusory contours, and their preferred directions are identical for both contours in unidirectional cells, whereas these directions are changed by 90 deg for real versus illusory contours in bidirectional cells. On the other hand, some pretectal neurons produce inhibitory (excitatory) after-responses to cessation of prolonged motion in the preferred (null) directions, whose time course is similar to that of the motion after-effect reported by humans. Because excitatory and inhibitory receptive fields of a pretectal cell overlap in visual space and possess opposite directionalities, after-responses to cessation of prolonged motion in one direction may create illusory motion in the opposite direction. It appears that illusory contours and motion could be detected at the earliest stage of central information processing and processed in bottom-up streams, and that the motion after-effect may result from functional interactions of excitatory and inhibitory receptive fields with opposite directionalities.

Tectal neurons signal impending collision of looming objects in the pigeon.

Although the optic tectum in non-mammals and its mammalian homolog, the superior colliculus, are involved in avoidance behaviors, whether and how tectal neurons respond to an object approaching on a collision course towards the animal remain unclear. Here we show by single unit recording that there exist three classes of looming-sensitive neurons in the pigeon tectal layer 13, which sends looming information to the nucleus rotundus or to the tectopontine system. The response onset time of tau cells is approximately constant whereas that for rho and eta cells depends on the square root of the diameter/velocity ratio of objects looming towards the animal, the cardioacceleration of which is also linearly related to the square root of this ratio. The receptive field of tectal cells is composed of an excitatory center and an inhibitory periphery, and this periphery does not inhibit responses to looming stimuli. These results suggest that three classes of tectal neurons are specified for detecting an object approaching on a collision course towards the animal, and that rho and eta cells may signal early warning of impending collision whereas tau cells initiate avoidance responses at a constant time before collision through the tectopontine system.