Dynamics of the disparity vergence fusion sustain component

The stereotypical vergence response to a step stimulus consists of two dynamic components: a high velocity fusion initiating component followed by a slower component that may mediate sustained fusion.  The initial component has been well-studied and is thought to be controlled by an open-loop mechanism. Less is known about the slow, or fusion sustaining component except that it must be feedback controlled to achieve the positional precision of sustained fusion.  Given the delays in disparity vergence control, a feedback control system is likely to exhibit oscillatory behavior.  Vergence responses to 4 deg step changes in target position were recorded in eight subjects. The slow component of each response was isolated manually using interactive graphics and the frequency spectrum determined.  The frequency spectra of all isolated slow vergence movements showed a large low frequency peak between 1.0 and 2.0 Hz and one or more higher frequency components.  The higher frequency components were found to be harmonics of the low frequency oscillation.  A feedback model of the slow component was developed consisting of a time delay, an integral/derivative controller and an oculomotor plant based on Robinson’s model.  Model simulations showed that a direction dependent asymmetry in the derivative element was primarily responsible for the higher frequency harmonic components. Simulations also showed that the base frequencies are primarily dependent on the time delay in the feedback control system. The fact that oscillatory behavior was found in all subjects provides strong support that the slow, fusion sustaining component is mediated by a feedback system

Error Correction in Vergence Eye Movements: Evidence Supporting Hering’s Law

In pure symmetrical vergence eye movements, a fusion initiating component quickly brings the eyes close to the desired position. A small error usually remains after this response which must be corrected to attain the small final vergence error (i.e., fixation disparity). Error correction will usually involve both version and version movements so possible mechanisms include: small saccades, smooth pursuit, symmetrical vergence, or some combination. Alternatively, an asymmetrical vergence or uniocular slow eye movement could be used to achieve the highly precise final position. Saccade-free late fusion sustaining components during the steady state to a symmetrical vergence step stimulus are analyzed using independent component analysis. Results suggest that fine correction is most likely the product of closely coordinated version and vergence components

Assessment of Dual-Mode and Switched-Channel Models with Experimental Vergence Responses

Controversy exists in the literature regarding the basic neural control structure that mediates convergence responses. This study constructed and simulated two models, the switched-channel feedback model and the dual-mode model consisting of preprogrammed with feedback control. Models were constructed and compared to experimental data. The stimuli consisted of 2 deg and 4 deg vergence steps. Both closed- and open-loop settings were utilized. After parameter adjustment, both models could accurately simulate step responses from subjects having a range of response dynamics. The model with a preprogrammed element required less parameter modification when stimulus amplitude changed. Both models could accurately simulate some attributes of vergence; however, neither model could represent the modifications commonly observed within the transient portion of the vergence response

Vergence fusion sustaining oscillations

Introduction:  Previous studies have shown that the slow, or fusion sustaining, component of disparity vergence contains oscillatory behavior.  Given the delays in disparity vergence control, a feedback control system would be expected to exhibit oscillations following the initial transient period.  This study extends the examination of this behavior to a wider range of frequencies and a larger number of subjects.  Methods:  Disparity vergence responses to symmetrical 4.0 deg step changes in target position were recorded in 15 subjects. Approximately three seconds of the late component of each response were isolated using interactive graphics and the frequency spectrum calculated.  Peaks in these spectra associated with oscillatory behavior were identified and examined.  Results: All subjects exhibited oscillatory behavior with primary frequencies ranging between 0.45 and 0.6 Hz; much lower than those identified in the earlier study.  All responses showed significant higher frequency components.  These higher frequency components were related in both frequency and amplitude with the primary frequency indicating that they are harmonics probably generated by nonlinearities in the neural control processes. A correlation was found across subjects between the amplitude of the primary frequency and the maximum velocity of the fusion initialing component probably due the gain of shared neural pathways. Conclusion:  Low frequency oscillatory behavior was found in all subjects adding support that the slow, or fusion sustaining, component is mediated by a feedback control. Data have clinical implications in that dysfunction in feedback control may manifest as additional vergence error which may be reflected in the frequency spectrum

Correction of Saccade-Induced Midline Errors in Responses to Pure Disparity Vergence Stimuli.

Purely symmetrical vergence stimuli aligned along the midline (cyclopean axis) require only a pure vergence response. Yet, in most responses saccades are observed and these saccades must either produce an error in the desired midline response or correct an error produced by asymmetry in the vergence response. A previous study (Semmlow, et al. 2008) has shown that the first saccade to appear in a response to a pure vergence stimulus usually increased the deviation from the midline, although all subjects (N = 12) had some responses where the initial saccade corrected a vergence induced midline error. This study focuses on those responses where the initial saccade produces an increased midline deviation and the resultant compensation that ultimately brings the eyes to the correct binocular position. This correction is accomplished by a higher level compensatory mechanism that uses offsetting asymmetrical vergence and/or corrective saccades. While responses consist of a mixture of the two compensatory mechanisms, the dominant mechanism is subject-dependent. Since fixation errors are quite small (minutes of arc), some feedback controlled physiological process involving smooth eye movements, and possibly saccades, must move the eyes to reduce binocular error to fixation disparity levels

Differentiation between Vergence and Saccadic Functional Activity within the Human Frontal Eye Fields and Midbrain Revealed through fMRI

Eye movement research has traditionally studied solely saccade and/or vergence eye movements by isolating these systems within a laboratory setting. While the neural correlates of saccadic eye movements are established, few studies have quantified the functional activity of vergence eye movements using fMRI. This study mapped the neural substrates of vergence eye movements and compared them to saccades to elucidate the spatial commonality and differentiation between these systems.The stimulus was presented in a block design where the 'off' stimulus was a sustained fixation and the 'on' stimulus was random vergence or saccadic eye movements. Data were collected with a 3T scanner. A general linear model (GLM) was used in conjunction with cluster size to determine significantly active regions. A paired t-test of the GLM beta weight coefficients was computed between the saccade and vergence functional activities to test the hypothesis that vergence and saccadic stimulation would have spatial differentiation in addition to shared neural substrates.Segregated functional activation was observed within the frontal eye fields where a portion of the functional activity from the vergence task was located anterior to the saccadic functional activity (z>2.3; p<0.03). An area within the midbrain was significantly correlated with the experimental design for the vergence but not the saccade data set. Similar functional activation was observed within the following regions of interest: the supplementary eye field, dorsolateral prefrontal cortex, ventral lateral prefrontal cortex, lateral intraparietal area, cuneus, precuneus, anterior and posterior cingulates, and cerebellar vermis. The functional activity from these regions was not different between the vergence and saccade data sets assessed by analyzing the beta weights of the paired t-test (p>0.2).Functional MRI can elucidate the differences between the vergence and saccade neural substrates within the frontal eye fields and midbrain

The Revolution Against Affirmative Action in California: Politics, Economics, and Proposition 209

We consider two possible explanations-economic anxiety and racial division for the appeal of Proposition 209 to California voters during the 1996 election. Voter support for this proposition has been attributed to racial differences in opinion and to economic anxiety caused by poor economic conditions in the state and the perceived threat that affirmative action presented in school admissions or the workplace. Because the presidential candidates campaigned on and debated the merits of affirmative action policy during this election, we incorporate this endogeneity into our analysis. We develop two competing hypotheses to explain voter behavior: (1) if voters are blaming affirmative action for the state's economic conditions, then voters who believe that California's economic condition is poor or who perceive that their personal financial situation is worse will be more likely to support Proposition 209; and (2) if voters are, instead, divided along more traditional racial lines on the merits of affirmative action (winners versus losers), then whites, males, Republicans, and conservatives will be more likely to support Proposition 209, and other ethnic group members, females, Democrats, and liberals will be more likely to oppose Proposition 209. To test these hypotheses, we analyze voter exit poll data from the 1996 California election. We utilize a two-stage logit model to allow for the endogeneity of candidate endorsements. We find support for the second of our two hypotheses. These findings cause us to conclude that racial division fueled by a fear of arbitrary exclusion prompted voter support for Proposition 209

Changes in the disparity vergence main sequence after treatment of symptomatic convergence insufficiency in children

This study investigates the underlying physiological mechanisms that may lead to improved outcomes for symptomatic convergence insufficiency (CI) patients after 12 weeks of office-based vergence/accommodation therapy (OBVAT) by evaluating the change in the main sequence of vergence and saccadic eye movements. In this prospective trial, 12 participants with symptomatic CI were recruited and treated with 12 weeks of OBVAT. Outcome measures included the objective assessment of the following: peak velocity, time to peak velocity, latency, response amplitude, and clinical changes in the near point of convergence (NPC), positive fusional vergence (PFV) and symptoms via the Convergence Insufficiency Symptom Survey (CISS). Ten of the twelve participants (83%) were categorized as “successful” and two were “improved” based on pre-determined published criteria (CISS, NPC, PFV). There were statistically significant changes in peak velocity, time to peak velocity, and response amplitude for both 4° and 6° symmetrical convergence and divergence eye movements. There was a significant change in the main sequence ratio for convergence post-OBVAT compared to baseline measurements (P=0.007) but not for divergence or saccadic responses. Phasic/step vergence movements adjust the underlying neural control of convergence and are critical within a vision therapy program for CI patients

Synaptic phosphorylated a-synuclein in dementia with Lewy bodies

Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated a-synuclein phosphorylated at Ser129. Although phosphorylated a-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other a-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated a-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer’s disease and five healthy control subjects to analyse the presence of phosphorylated a-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or post-synaptic terminals were analysed. We found that phosphorylated a-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (50.16 mm3). Between 19% and 25% of phosphorylated a-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated a-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated a-synuclein aggregation in synapses (pre4pre + post4post-synaptic) was observed. These results indicate that phosphorylated a-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated a-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated a-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.Peer ReviewedPostprint (author's final draft

Molecular pathways leading to loss of skeletal muscle mass in cancer cachexia can findings from animal models be translated to humans?

Background: Cachexia is a multi-factorial, systemic syndrome that especially affects patients with cancer of the gastrointestinal tract, and leads to reduced treatment response, survival and quality of life. The most important clinical feature of cachexia is the excessive wasting of skeletal muscle mass. Currently, an effective treatment is still lacking and the search for therapeutic targets continues. Even though a substantial number of animal studies have contributed to a better understanding of the underlying mechanisms of the loss of skeletal muscle mass, subsequent clinical trials of potential new drugs have not yet yielded any effective treatment for cancer cachexia. Therefore, we questioned to which degree findings from animal studies can be translated to humans in clinical practice and research. Discussion: A substantial amount of animal studies on the molecular mechanisms of muscle wasting in cancer cachexia has been conducted in recent years. This extensive review of the literature showed that most of their observations could not be consistently reproduced in studies on human skeletal muscle samples. However, studies on human material are scarce and limited in patient numbers and homogeneity. Therefore, their results have to be interpreted critically. Summary: More research is needed on human tissue samples to clarify the signaling pathways that lead to skeletal muscle loss, and to confirm pre-selected drug targets from animal models in clinical trials. In addition, improved diagnostic tools and standardized clinical criteria for cancer cachexia are needed to conduct standardized, randomized controlled trials of potential drug candidates in the future