Correlated structure of neuronal firing in macaque visual cortex limits information for binocular depth discrimination.

Variability in cortical neural activity potentially limits sensory discriminations. Theoretical work shows that information required to discriminate two similar stimuli is limited by the correlation structure of cortical variability. We investigated these information-limiting correlations by recording simultaneously from visual cortical areas primary visual cortex (V1) and extrastriate area V4 in macaque monkeys performing a binocular, stereo depth discrimination task. Within both areas, noise correlations on a rapid temporal scale (20-30 ms) were stronger for neuron pairs with similar selectivity for binocular depth, meaning that these correlations potentially limit information for making the discrimination. Between-area correlations (V1 to V4) were different, being weaker for neuron pairs with similar tuning and having a slower temporal scale (100+ ms). Fluctuations in these information-limiting correlations just prior to the detection event were associated with changes in behavioral accuracy. Although these correlations limit the recovery of information about sensory targets, their impact may be curtailed by integrative processing of signals across multiple brain areas.NEW & NOTEWORTHY Correlated noise reduces the stimulus information in visual cortical neurons during experimental performance of binocular depth discriminations. The temporal scale of these correlations is important. Rapid (20-30 ms) correlations reduce information within and between areas V1 and V4, whereas slow (>100 ms) correlations between areas do not. Separate cortical areas appear to act together to maintain signal fidelity. Rapid correlations reduce the neuronal signal difference between stimuli and adversely affect perceptual discrimination.

The Magnitude, But Not the Sign, of MT Single-Trial Spike-Time Correlations Predicts Motion Detection Performance.

Spike-time correlations capture the short timescale covariance between the activity of neurons on a single trial. These correlations can significantly vary in magnitude and sign from trial to trial, and have been proposed to contribute to information encoding in visual cortex. While monkeys performed a motion-pulse detection task, we examined the behavioral impact of both the magnitude and sign of single-trial spike-time correlations between two nonoverlapping pools of middle temporal (MT) neurons. We applied three single-trial measures of spike-time correlation between our multiunit MT spike trains (Pearson's, absolute value of Pearson's, and mutual information), and examined the degree to which they predicted a subject's performance on a trial-by-trial basis. We found that on each trial, positive and negative spike-time correlations were almost equally likely, and, once the correlational sign was accounted for, all three measures were similarly predictive of behavior. Importantly, just before the behaviorally relevant motion pulse occurred, single-trial spike-time correlations were as predictive of the performance of the animal as single-trial firing rates. While firing rates were positively associated with behavioral outcomes, the presence of either strong positive or negative correlations had a detrimental effect on behavior. These correlations occurred on short timescales, and the strongest positive and negative correlations modulated behavioral performance by ∼9%, compared with trials with no correlations. We suggest a model where spike-time correlations are associated with a common noise source for the two MT pools, which in turn decreases the signal-to-noise ratio of the integrated signals that drive motion detection.SIGNIFICANCE STATEMENT Previous work has shown that spike-time correlations occurring on short timescales can affect the encoding of visual inputs. Although spike-time correlations significantly vary in both magnitude and sign across trials, their impact on trial-by-trial behavior is not fully understood. Using neural recordings from area MT (middle temporal) in monkeys performing a motion-detection task using a brief stimulus, we found that both positive and negative spike-time correlations predicted behavioral responses as well as firing rate on a trial-by-trial basis. We propose that strong positive and negative spike-time correlations decreased behavioral performance by reducing the signal-to-noise ratio of integrated MT neural signals.

Neural architectures for stereo vision.

Stereoscopic vision delivers a sense of depth based on binocular information but additionally acts as a mechanism for achieving correspondence between patterns arriving at the left and right eyes. We analyse quantitatively the cortical architecture for stereoscopic vision in two areas of macaque visual cortex. For primary visual cortex V1, the result is consistent with a module that is isotropic in cortical space with a diameter of at least 3 mm in surface extent. This implies that the module for stereo is larger than the repeat distance between ocular dominance columns in V1. By contrast, in the extrastriate cortical area V5/MT, which has a specialized architecture for stereo depth, the module for representation of stereo is about 1 mm in surface extent, so the representation of stereo in V5/MT is more compressed than V1 in terms of neural wiring of the neocortex. The surface extent estimated for stereo in V5/MT is consistent with measurements of its specialized domains for binocular disparity. Within V1, we suggest that long-range horizontal, anatomical connections form functional modules that serve both binocular and monocular pattern recognition: this common function may explain the distortion and disruption of monocular pattern vision observed in amblyopia.This article is part of the themed issue 'Vision in our three-dimensional world'.

Dynamics of the functional link between area MT LFPs and motion detection.

The evolution of a visually guided perceptual decision results from multiple neural processes, and recent work suggests that signals with different neural origins are reflected in separate frequency bands of the cortical local field potential (LFP). Spike activity and LFPs in the middle temporal area (MT) have a functional link with the perception of motion stimuli (referred to as neural-behavioral correlation). To cast light on the different neural origins that underlie this functional link, we compared the temporal dynamics of the neural-behavioral correlations of MT spikes and LFPs. Wide-band activity was simultaneously recorded from two locations of MT from monkeys performing a threshold, two-stimuli, motion pulse detection task. Shortly after the motion pulse occurred, we found that high-gamma (100-200 Hz) LFPs had a fast, positive correlation with detection performance that was similar to that of the spike response. Beta (10-30 Hz) LFPs were negatively correlated with detection performance, but their dynamics were much slower, peaked late, and did not depend on stimulus configuration or reaction time. A late change in the correlation of all LFPs across the two recording electrodes suggests that a common input arrived at both MT locations prior to the behavioral response. Our results support a framework in which early high-gamma LFPs likely reflected fast, bottom-up, sensory processing that was causally linked to perception of the motion pulse. In comparison, late-arriving beta and high-gamma LFPs likely reflected slower, top-down, sources of neural-behavioral correlation that originated after the perception of the motion pulse.

ROC-based estimates of neural-behavioral covariations using matched filters.

Correlations between responses in visual cortex and perceptual performance help draw a functional link between neural activity and visually guided behavior. These correlations are commonly derived with ROC-based neural-behavioral covariances (referred to as choice or detect probability) using boxcar analysis windows. Although boxcar windows capture the covariation between neural activity and behavior during steady-state stimulus presentations, they are not optimized to capture these correlations during short time-varying visual inputs. In this study, we implemented a matched-filter technique, combined with cross-validation, to improve the estimation of ROC-based neural-behavioral covariance under short and dynamic stimulus conditions. We show that this approach maximizes the area under the ROC curve and converges to the true neural-behavioral covariance using a Poisson spiking model. We also demonstrate that the matched filter, combined with cross-validation, reveals the dynamics of the neural-behavioral covariations of individual MT neurons during the detection of a brief motion stimulus.

The functional link between area MT neural fluctuations and detection of a brief motion stimulus.

Fluctuations of neural firing rates in visual cortex are known to be correlated with variations in perceptual performance. It is important to know whether these fluctuations are functionally linked to perception in a causal manner or instead reflect non-causal processes that arise after the perceptual decision is made. We recorded from middle temporal (MT) neurons from monkey subjects while they detected the random occurrence of a brief 50 ms motion pulse that occurred in either of two (or simultaneously in both) random dot patches located in the same hemisphere. The receptive field parameters of the motion pulse were matched to that preferred by each MT neuron under study. This task contained uncertainty in both space and time because, on any given trial, the subjects did not know which patch would contain the motion pulse or when the motion pulse would occur. Covariations between MT activity and behavior began just before the motion pulse onset and peaked at the maximum neural response. These neural-behavioral covariations were strongest when only one patch contained the motion pulse and were still weakly present when a patch did not contain a motion pulse. A feedforward temporal integration model with two independent detector channels captured both the detection performance and evolution of the neural-behavior covariations over time and stimulus condition. The results suggest that, when detecting a brief visual stimulus, there is a causal relationship between fluctuations in neural activity and variations in behavior across trials.

The effect of microsaccades on the correlation between neural activity and behavior in middle temporal, ventral intraparietal, and lateral intraparietal areas.

It is widely reported that the activity of single neurons in visual cortex is correlated with the perceptual decision of the subject. The strength of this correlation has implications for the neuronal populations generating the percepts. Here we asked whether microsaccades, which are small, involuntary eye movements, contribute to the correlation between neural activity and behavior. We analyzed data from three different visual detection experiments, with neural recordings from the middle temporal (MT), lateral intraparietal (LIP), and ventral intraparietal (VIP) areas. All three experiments used random dot motion stimuli, with the animals required to detect a transient or sustained change in the speed or strength of motion. We found that microsaccades suppressed neural activity and inhibited detection of the motion stimulus, contributing to the correlation between neural activity and detection behavior. Microsaccades accounted for as much as 19% of the correlation for area MT, 21% for area LIP, and 17% for VIP. While microsaccades only explain part of the correlation between neural activity and behavior, their effect has implications when considering the neuronal populations underlying perceptual decisions.

Relationship between prior course of illness and neuroanatomic structures in bipolar disorder: a preliminary study.

OBJECTIVE: In this preliminary study, we examined the relationships between prior course and severity of illness and size of the hippocampus, temporal lobes, and third and lateral ventricles in patients with bipolar disorder. BACKGROUND: The few studies that have investigated relationships between course of illness measures and neuroanatomic structures in patients with bipolar disorder found divergent results. METHOD: Twenty-six outpatients, who met Diagnostic and Statistical Manual, Third Edition - Revised (DSM-III-R) criteria for bipolar disorder, received a magnetic resonance imaging (MRI) scan, from which volumes of the temporal lobes, hippocampi, third ventricle, and areas of the lateral ventricles were calculated. Prior course of illness variables were determined using the NIMH Life-Chart Method and were correlated to the volumetric measures of neuroanatomic structures using multiple regression analyses. RESULTS: A longer duration of illness was paradoxically associated with a larger left temporal lobe volume whether patients with a history of substance abuse were removed from the analyses. CONCLUSIONS: Additional studies are needed to both replicate and further examine the association of prior course of illness and larger hippocampal and ventricular volumes in bipolar disorder.

Neuroleptic exposure in bipolar outpatients in a research setting.

The study purpose was to determine the extent of neuroleptic exposure in bipolar outpatients maintained on mood-stabilizing medications and any clinical correlates associated with this exposure. Data on medication and severity of illness were gathered from the records (prospective and retrospective) of 70 bipolar patients involved in outpatient research studies at the National Institute of Mental Health (NIMH). The percentage of patients requiring neuroleptic treatment, percentage of time on neuroleptics during the period of observation, total dose of neuroleptics in chlorpromazine (CPZ) equivalency, and number of neuroleptic trials were among the variables calculated. Regression analyses and analyses of variance (ANOVAs) were performed to assess the relationships between neuroleptic exposure and clinical course. Forty-five patients (64.3%) had a neuroleptic trial during the prospective study. Subjects exposed to neuroleptics spent, on average, 15.4% (median, 6.0%) of the time in study on neuroleptic treatment, and were administered, on average, a total of 11,770.5 mg (median, 1,621.9 mg) of neuroleptics (in CPZ equivalency) per year in the prospective study. As expected, bipolar I compared with bipolar II patients had significantly higher neuroleptic exposure by a number of measures. The number of hospitalizations for mania prior to study entry was associated with greater prospective neuroleptic use during the study. Despite maintenance treatment with one or more moodstabilizing agents, we found a relatively high need for adjunctive neuroleptic medication even in this sample of high-functioning bipolar outpatients. These results highlight the need for the study of alternatives, as well as more effective primary mood-stabilizing agents.

A preliminary study of the relation of neuropsychological performance to neuroanatomic structures in bipolar disorder.

OBJECTIVE: To investigate the relation between neuropsychological dysfunction and volumetric measures of neuroanatomic structures in patients with bipolar disorder. BACKGROUND: Previous research suggests that neuropsychological deficits are associated with neuroanatomic changes in patients with bipolar disorder. METHOD: Twenty-six outpatients who met Diagnostic and Statistical Manual, Third Edition-Revised criteria for bipolar disorder were administered a battery of neuropsychological tests that assessed memory, abstracting ability, psychomotor performance, sustained attention, and intelligence. Patients also received a magnetic resonance imaging scan, from which volumes of the temporal lobes, hippocampus, third ventricle, and areas of the lateral ventricles were calculated. Using multiple regression analyses, neuroanatomic structures were compared with neuropsychological test variables. RESULTS: Data suggest that a larger right hippocampal volume is associated with poorer neuropsychological functioning. CONCLUSIONS: Further studies are needed to both replicate and examine the relation between potential mechanisms of neuroanatomic alterations and neuropsychological dysfunction in patients with bipolar disorder.

Association between lower serum free T4 and greater mood instability and depression in lithium-maintained bipolar patients.

OBJECTIVE: This investigation evaluated the relationship between changes in thyroid indices and mood stability during lithium and carbamazepine prophylaxis for bipolar disorder. METHOD: In the first 2 years, 30 patients with bipolar mood disorder were randomly assigned to 1 year of lithium and then 1 year of carbamazepine, or vice versa; in the third year, they received lithium plus carbamazepine. By stepwise regression analysis, the degree and timing of lithium- and carbamazepine-induced thyroid changes and their subsequent relationship to long-term mood stability were evaluated. RESULTS: During the lithium phase, there was a significant inverse relationship between morbidity and mean serum level of free T4, i.e., a lower mean serum level of free T4 was associated with more affective episodes and greater severity of depression as shown by the Beck Depression Inventory. During the carbamazepine phase, there was an inverse relationship between mean level of total T4 and global severity rating. During the combination phase, no relationships between thyroid indices and clinical outcome were significant. CONCLUSIONS: In the lithium phase, a low level of free T4 was associated with more affective episodes and greater severity of depression. Whether this mood instability is causally related to low free T4 levels and whether it can be attenuated with T4 replacement remain to be studied in a controlled setting.

Antidepressant discontinuation-related mania: critical prospective observation and theoretical implications in bipolar disorder.

BACKGROUND: Development of manic symptoms on antidepressant discontinuation has primarily been reported in unipolar patients. This case series presents preliminary evidence for a similar phenomenon in bipolar patients. METHOD: Prospectively obtained life chart ratings of 73 bipolar patients at the National Institute of Mental Health were reviewed for manic episodes that emerged during antidepressant taper or discontinuation. Medical records were utilized as a corroborative resource. Six cases of antidepressant discontinuation-related mania were identified and critically evaluated. RESULTS: All patients were taking conventional mood stabilizers. The patients were on antidepressant treatment a mean of 6.5 months prior to taper, which lasted an average of 20 days (range, 1-43 days). First manic symptoms emerged, on average, 2 weeks into the taper (range, 1-23 days). These 6 cases of antidepressant discontinuation-related mania involved 3 selective serotonin reuptake inhibitors (SSRIs), 2 tricyclic antidepressants (TCAs), and 1 serotonin-norepinephrine reuptake inhibitor. Mean length of the ensuing manic episode was 27.8 days (range, 12-49 days). Potential confounds such as antidepressant induction, phenomenological misdiagnosis of agitated depression, physiologic drug withdrawal syndrome, and course of illness were carefully evaluated and determined to be noncontributory. CONCLUSION: These 6 cases suggest a paradoxical effect whereby antidepressant discontinuation actually induces mania in spite of adequate concomitant mood-stabilizing treatment. These preliminary observations, if replicated in larger and controlled prospective studies, suggest the need for further consideration of the potential biochemical mechanisms involved so that new preventive treatment approaches can be assessed.

Relationship between prior course of illness and neuropsychological functioning in patients with bipolar disorder.

BACKGROUND: This study investigated the relationship between prior course of illness and neuropsychological deficits in relatively high functioning outpatients with bipolar disorder. METHOD: Forty-nine bipolar I or II patients, in a relatively euthymic state during treatment with mood stabilizers, were administered neuropsychological tests that assessed a variety of functions, including verbal memory, sustained attention and vigilance, and intelligence. A detailed retrospective life chart was completed for each patient using the NIMH Life Chart Method" to define variables reflecting duration and severity of illness, and frequency of episodes. RESULTS: Stepwise multiple regression analyses show that several different measures of a more severe course of prior illness related to greater duration and a larger number of affective episodes and hospitalizations were associated with poorer performance on tests of abstraction, attention and memory. CONCLUSION: The results indicate that bipolar patients with a more severe prior course of illness and a greater number of affective episodes have more impaired neuropsychological functioning. The direction of causality and the pathophysiological mechanisms remain to be explored.

Comparative prophylactic efficacy of lithium, carbamazepine, and the combination in bipolar disorder.

BACKGROUND: We compared the prophylactic efficacy of lithium, carbamazepine, and the combination and identified possible clinical markers of response. METHOD: Fifty-two outpatients who met DSM-III-R criteria for bipolar illness were randomly assigned in a double-blind design for an intended 1 year of treatment with lithium or carbamazepine, a crossover to the opposite drug in the second year, and then a third year on the combination. Patients received monthly detailed evaluations, and daily life chart ratings of the degree of functional incapacity associated with mania or depression were completed. RESULTS: For evaluable patients: 13 (31.0%) of 42 failed to complete a full year of lithium therapy owing to lack of efficacy, and 2 dropped out because of side effects; 13 (37.1%) of 35 withdrew from carbamazepine within the first year owing to lack of efficacy, and 10 dropped out because of side effects (9 of the 10 had a rash); 7 (24.1%) of 29 withdrew from the combination therapy owing to lack of efficacy. The percentage of the evaluable patients who had marked or moderate improvement on the Clinical Global Impressions scale was 33.3% on lithium. 31.4% on carbamazepine, and 55.2% on the combination treatment, which was not significantly different. By a variety of measures, lithium was more effective than carbamazepine in the prophylaxis of mania. Patients with a past history of rapid cycling did poorly on monotherapy (28.0% responded to lithium; 19.0% responded to carbamazepine), but significantly better on the combination (56.3%, p < .05). CONCLUSION: These prospective, randomized data suggest a high incidence of inadequate response to either mood stabilizer or their combination despite use of adjunctive agents as needed. Additional novel treatment regimens are needed to better decrease affective morbidity in large numbers of bipolar outpatients.

Preliminary evidence of the reliability and validity of the prospective life-chart methodology (LCM-p).

This article describes the use of the NIMH prospective life-charting methodology (NIMH LCM-p) in the context of a formal double-blind, clinical trial and provides preliminary evidence of its reliability and validity. Subjects included in this report were 30 outpatients with bipolar I and II disorder who completed the first 2 years of a long-term maintenance study: 1 year on carbamazepine or lithium and a crossover to the other in the second year. The LCM-p follows the same types of guidelines and principles utilized in the previously described retrospective life-chart process, allowing for continuity of illness assessment prior and subsequent to study entry. In the LCM-p, daily ratings of severity of mood symptoms based on the degree of associated functional incapacity, provide a more detailed topography of manic and depressive fluctuations. Inter-rater reliability was examined by comparing the severity of daily LCM-p ratings assigned by two raters. In order to assess the validity, we correlated the LCM-p ratings with well-standardized scales, including Hamilton and Beck Depression Ratings, Young Mania Ratings and the Global Assessment Scale (GAS). The Kappa scores for inter-rater reliability demonstrated significant and satisfactory strength of agreement with no fall off over 14 days prior to the rating interview. Strong correlations were found: (1) between the LCM-p average severity for depression rating and the mean Hamilton Depression Rating (r = 0.86, p < .001), and the Beck Depression Inventory (r = 0.73, p < .001); 2) between the LCM-p average severity for mania rating and the Young Mania Rating Scale (r = 0.61, p < .001); and (3) between the LCM-p average severity and the GAS (r = -0.81, p < .001). These preliminary data suggest the reliability and validity of the NIMH-LCM-p in assessing manic and depressive episode severity. It also provides a useful continuous daily measure of affective illness-related symptom fluctuations that allows for detailed prospective assessment of frequency and pattern of illness, treatment response, and continuity with retrospective life chart assessments.

Psychosensory symptoms in bipolar disorder.

This study investigated psychosensory symptoms and their relationship to retrospective and prospective courses of illness, as well as therapeutic outcomes, in patients with bipolar disorder. Using the Silberman-Post Psychosensory Rating Scale (SP-PSRS), psychosensory symptoms were assessed in 51 patients who met Diagnostic and Statistical Manual, 3rd Edition-Revised (DSM-III-R) criteria for bipolar disorder and in 39 healthy, normal controls. Patients with bipolar disorder were enrolled in a 3-year, double-blind, randomized study comparing the prophylactic efficacy of lithium or carbamazepine in the first year, a crossover to the other drug in the second year, and the combination of both medications in the third year. Psychosensory scores from patients with bipolar disorder were compared with scores from healthy controls and with a variety of retrospective and prospective course of illness and treatment variables. Psychosensory symptoms occurred frequently in patients with bipolar I and II disorders, but were rare in healthy controls. When depressed, patients with bipolar II disorder (n = 23) reported more psychosensory symptoms when compared to patients with bipolar I disorder (n = 28), and those with a history of rapid cycling (n = 29) reported more psychosensory symptoms when compared to patients without a history of rapid cycling (n = 21). Psychosensory symptoms were not related to response to carbamazepine, lithium, or the combination of both drugs. Although the presence of psychosensory symptoms is associated with some bipolar subtypes (patients with bipolar II disorder and patients with a history of rapid cycling), they do not appear to predict treatment response. Further studies are needed to assess the pathophysiologic implications of the presence of psychosensory symptoms and their potential implications, if any, for directing therapeutics.

Valproate prophylaxis in a prospective clinical trial of refractory bipolar disorder.

OBJECTIVE: The authors studied the efficacy of valproate plus lithium and of triple therapy with lithium, carbamazepine, and valproate in refractory bipolar illness. METHOD: The subjects were 24 bipolar outpatients who had completed an intended 3-year crossover study comparing lithium, carbamazepine, and their combination. Patients entered a 1-year phase of valproate plus lithium because of inadequate response or major side effects, and patients with inadequate responses were offered an additional year of treatment with all three mood-stabilizing drugs. RESULTS: Six (33%) of the 18 evaluable patients had moderate to marked responses to valproate plus lithium; four of these six had not responded to any previous treatment condition. Three of seven patients responded to triple therapy, although only one response was marked. CONCLUSIONS: Some outpatients with bipolar disorder refractory to lithium and carbamazepine received clinically relevant prophylactic benefit from valproate when used with lithium or in triple therapy.

High levels of Gs alpha in platelets of euthymic patients with bipolar affective disorder.

OBJECTIVE: Previous investigations have suggested the involvement of signal-transducing guanine-nucleotide-binding proteins (G proteins) both in the mechanism of action of lithium and in the pathophysiology of bipolar affective disorder. To determine whether such G protein abnormalities are a trait phenomenon, the authors investigated the levels of G protein alpha subunits in platelets and lymphocytes of euthymic patients with bipolar affective disorder. METHOD: Selective antibodies were used to quantitate levels of G protein alpha subunits regulating adenylylcyclase activity (Gs alpha-both 45- and 52-kDa forms- and Gil-2 alpha) and those regulating phosphoinositide turnover (Gq/11 alpha) in both platelets and lymphocytes of 44 euthymic patients with bipolar affective disorder and 27 matched comparison subjects. RESULTS: Levels of both Gs alpha 45 and Gs alpha 52 were higher in the platelets of the euthymic bipolar patients (both bipolar I and bipolar II) than in those of the comparison subjects. CONCLUSIONS: These findings are consistent with previous reports of high Gs alpha levels in bipolar affective disorder and, furthermore, suggest that such levels may be a trait abnormality for this condition.