Retrospective analysis of Braak stage- and APOE4 allele-dependent associations between MR spectroscopy and markers of tau and neurodegeneration in cognitively unimpaired elderly.

PURPOSE: The pathological hallmarks of Alzheimer's disease (AD), amyloid, tau, and associated neurodegeneration, are present in the cortical gray matter (GM) years before symptom onset, and at significantly greater levels in carriers of the apolipoprotein E4 (APOE4) allele. Their respective biomarkers, A/T/N, have been found to correlate with aspects of brain biochemistry, measured with magnetic resonance spectroscopy (MRS), indicating a potential for MRS to augment the A/T/N framework for staging and prediction of AD. Unfortunately, the relationships between MRS and A/T/N biomarkers are unclear, largely due to a lack of studies examining them in the context of the spatial and temporal model of T/N progression. Advanced MRS acquisition and post-processing approaches have enabled us to address this knowledge gap and test the hypotheses, that glutamate-plus-glutamine (Glx) and N-acetyl-aspartate (NAA), metabolites reflecting synaptic and neuronal health, respectively, measured from regions on the Braak stage continuum, correlate with: (i) cerebrospinal fluid (CSF) p-tau181 level (T), and (ii) hippocampal volume or cortical thickness of parietal lobe GM (N). We hypothesized that these correlations will be moderated by Braak stage and APOE4 genotype. METHODS: We conducted a retrospective imaging study of 34 cognitively unimpaired elderly individuals who received APOE4 genotyping and lumbar puncture from pre-existing prospective studies at the NYU Grossman School of Medicine between October 2014 and January 2019. Subjects returned for their imaging exam between April 2018 and February 2020. Metabolites were measured from the left hippocampus (Braak II) using a single-voxel semi-adiabatic localization by adiabatic selective refocusing sequence; and from the bilateral posterior cingulate cortex (PCC; Braak IV), bilateral precuneus (Braak V), and bilateral precentral gyrus (Braak VI) using a multi-voxel echo-planar spectroscopic imaging sequence. Pearson and Spearman correlations were used to examine the relationships between absolute levels of choline, creatine, myo-inositol, Glx, and NAA and CSF p-tau181, and between these metabolites and hippocampal volume or parietal cortical thicknesses. Covariates included age, sex, years of education, Fazekas score, and months between CSF collection and MRI exam. RESULTS: There was a direct correlation between hippocampal Glx and CSF p-tau181 in APOE4 carriers (Pearson's r = 0.76, p = 0.02), but not after adjusting for covariates. In the entire cohort, there was a direct correlation between hippocampal NAA and hippocampal volume (Spearman's r = 0.55, p = 0.001), even after adjusting for age and Fazekas score (Spearman's r = 0.48, p = 0.006). This relationship was observed only in APOE4 carriers (Pearson's r = 0.66, p = 0.017), and was also retained after adjustment (Pearson's r = 0.76, p = 0.008; metabolite-by-carrier interaction p = 0.03). There were no findings in the PCC, nor in the negative control (late Braak stage) regions of the precuneus and precentral gyrus. CONCLUSIONS: Our findings are in line with the spatially- and temporally-resolved Braak staging model of pathological severity in which the hippocampus is affected earlier than the PCC. The correlations, between MRS markers of synaptic and neuronal health and, respectively, T and N pathology, were found exclusively within APOE4 carriers, suggesting a connection with AD pathological change, rather than with normal aging. We therefore conclude that MRS has the potential to augment early A/T/N staging, with the hippocampus serving as a more sensitive MRS target compared to the PCC.

Screening for PTSD and TBI in Veterans using Routine Clinical Laboratory Blood Tests.

Post-traumatic stress disorder (PTSD) is a mental disorder diagnosed by clinical interviews, self-report measures and neuropsychological testing. Traumatic brain injury (TBI) can have neuropsychiatric symptoms similar to PTSD. Diagnosing PTSD and TBI is challenging and more so for providers lacking specialized training facing time pressures in primary care and other general medical settings. Diagnosis relies heavily on patient self-report and patients frequently under-report or over-report their symptoms due to stigma or seeking compensation. We aimed to create objective diagnostic screening tests utilizing Clinical Laboratory Improvement Amendments (CLIA) blood tests available in most clinical settings. CLIA blood test results were ascertained in 475 male veterans with and without PTSD and TBI following warzone exposure in Iraq or Afghanistan. Using random forest (RF) methods, four classification models were derived to predict PTSD and TBI status. CLIA features were selected utilizing a stepwise forward variable selection RF procedure. The AUC, accuracy, sensitivity, and specificity were 0.730, 0.706, 0.659, and 0.715, respectively for differentiating PTSD and healthy controls (HC), 0.704, 0.677, 0.671, and 0.681 for TBI vs. HC, 0.739, 0.742, 0.635, and 0.766 for PTSD comorbid with TBI vs HC, and 0.726, 0.723, 0.636, and 0.747 for PTSD vs. TBI. Comorbid alcohol abuse, major depressive disorder, and BMI are not confounders in these RF models. Markers of glucose metabolism and inflammation are among the most significant CLIA features in our models. Routine CLIA blood tests have the potential for discriminating PTSD and TBI cases from healthy controls and from each other. These findings hold promise for the development of accessible and low-cost biomarker tests as screening measures for PTSD and TBI in primary care and specialty settings.

Association between lower body temperature and increased tau pathology in cognitively normal older adults.

BACKGROUND: Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by a small (<1 °C) decrease in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults. METHODS: Tb was continuously measured with ingestible telemetry sensors for 48 h. This period included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later. RESULTS: Lower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF P-tau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05). CONCLUSIONS: These results, the first available for human, suggest that lower Tb in older adults may be associated with increased tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation. CLINICAL TRIAL NUMBER: NCT03053908.

Association of Psychiatric Disorders With Mortality Among Patients With COVID-19.

Importance: To date, the association of psychiatric diagnoses with mortality in patients infected with coronavirus disease 2019 (COVID-19) has not been evaluated. Objective: To assess whether a diagnosis of a schizophrenia spectrum disorder, mood disorder, or anxiety disorder is associated with mortality in patients with COVID-19. Design, Setting, and Participants: This retrospective cohort study assessed 7348 consecutive adult patients for 45 days following laboratory-confirmed COVID-19 between March 3 and May 31, 2020, in a large academic medical system in New York. The final date of follow-up was July 15, 2020. Patients without available medical records before testing were excluded. Exposures: Patients were categorized based on the following International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnoses before their testing date: (1) schizophrenia spectrum disorders, (2) mood disorders, and (3) anxiety disorders. Patients with these diagnoses were compared with a reference group without psychiatric disorders. Main Outcomes and Measures: Mortality, defined as death or discharge to hospice within 45 days following a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result. Results: Of the 26 540 patients tested, 7348 tested positive for SARS-CoV-2 (mean [SD] age, 54 [18.6] years; 3891 [53.0%] women). Of eligible patients with positive test results, 75 patients (1.0%) had a history of a schizophrenia spectrum illness, 564 (7.7%) had a history of a mood disorder, and 360 (4.9%) had a history of an anxiety disorder. After adjusting for demographic and medical risk factors, a premorbid diagnosis of a schizophrenia spectrum disorder was significantly associated with mortality (odds ratio [OR], 2.67; 95% CI, 1.48-4.80). Diagnoses of mood disorders (OR, 1.14; 95% CI, 0.87-1.49) and anxiety disorders (OR, 0.96; 95% CI, 0.65-1.41) were not associated with mortality after adjustment. In comparison with other risk factors, a diagnosis of schizophrenia ranked behind only age in strength of an association with mortality. Conclusions and Relevance: In this cohort study of adults with SARS-CoV-2-positive test results in a large New York medical system, adults with a schizophrenia spectrum disorder diagnosis were associated with an increased risk for mortality, but those with mood and anxiety disorders were not associated with a risk of mortality. These results suggest that schizophrenia spectrum disorders may be a risk factor for mortality in patients with COVID-19.

Pre-deployment risk factors for PTSD in active-duty personnel deployed to Afghanistan: a machine-learning approach for analyzing multivariate predictors.

Active-duty Army personnel can be exposed to traumatic warzone events and are at increased risk for developing post-traumatic stress disorder (PTSD) compared with the general population. PTSD is associated with high individual and societal costs, but identification of predictive markers to determine deployment readiness and risk mitigation strategies is not well understood. This prospective longitudinal naturalistic cohort study-the Fort Campbell Cohort study-examined the value of using a large multidimensional dataset collected from soldiers prior to deployment to Afghanistan for predicting post-deployment PTSD status. The dataset consisted of polygenic, epigenetic, metabolomic, endocrine, inflammatory and routine clinical lab markers, computerized neurocognitive testing, and symptom self-reports. The analysis was computed on active-duty Army personnel (N = 473) of the 101st Airborne at Fort Campbell, Kentucky. Machine-learning models predicted provisional PTSD diagnosis 90-180 days post deployment (random forest: AUC = 0.78, 95% CI = 0.67-0.89, sensitivity = 0.78, specificity = 0.71; SVM: AUC = 0.88, 95% CI = 0.78-0.98, sensitivity = 0.89, specificity = 0.79) and longitudinal PTSD symptom trajectories identified with latent growth mixture modeling (random forest: AUC = 0.85, 95% CI = 0.75-0.96, sensitivity = 0.88, specificity = 0.69; SVM: AUC = 0.87, 95% CI = 0.79-0.96, sensitivity = 0.80, specificity = 0.85). Among the highest-ranked predictive features were pre-deployment sleep quality, anxiety, depression, sustained attention, and cognitive flexibility. Blood-based biomarkers including metabolites, epigenomic, immune, inflammatory, and liver function markers complemented the most important predictors. The clinical prediction of post-deployment symptom trajectories and provisional PTSD diagnosis based on pre-deployment data achieved high discriminatory power. The predictive models may be used to determine deployment readiness and to determine novel pre-deployment interventions to mitigate the risk for deployment-related PTSD.

Anterior Hippocampal-Cortical Functional Connectivity Distinguishes Antipsychotic Naïve First-Episode Psychosis Patients From Controls and May Predict Response to Second-Generation Antipsychotic Treatment.

BACKGROUND: Converging evidence implicates the anterior hippocampus in the proximal pathophysiology of schizophrenia. Although resting state functional connectivity (FC) holds promise for characterizing anterior hippocampal circuit abnormalities and their relationship to treatment response, this technique has not yet been used in first-episode psychosis (FEP) patients in a manner that distinguishes the anterior from posterior hippocampus. METHODS: We used masked-hippocampal-group-independent component analysis with dual regression to contrast subregional hippocampal-whole brain FC between healthy controls (HCs) and antipsychotic naïve FEP patients (N = 61, 36 female). In a subsample of FEP patients (N = 27, 15 female), we repeated this analysis following 8 weeks of second-generation antipsychotic treatment and explored whether baseline FC predicted treatment response using random forest. RESULTS: Relative to HC, untreated FEP subjects displayed reproducibly lower FC between the left anteromedial hippocampus and cortical regions including the anterior cingulate and insular cortex (P < .05, corrected). Anteromedial hippocampal FC increased in FEP patients following treatment (P < .005), and no longer differed from HC. Random forest analysis showed baseline anteromedial hippocampal FC with four brain regions, namely the insular-opercular cortex, superior frontal gyrus, precentral gyrus, and postcentral gyrus predicted treatment response (area under the curve = 0.95). CONCLUSIONS: Antipsychotic naïve FEP is associated with lower FC between the anterior hippocampus and cortical regions previously implicated in schizophrenia. Preliminary analysis suggests that random forest models based on hippocampal FC may predict treatment response in FEP patients, and hence could be a useful biomarker for treatment development.

Clozapine, chlorpromazine and risperidone dose-dependently reduce emotional hyperthermia, a biological marker of salience.

RATIONALE: We recently introduced a new rat model of emotional hyperthermia in which a salient stimulus activates brown adipose tissue (BAT) thermogenesis and tail artery constriction. Antipsychotic drugs, both classical and second generation, act to reduce excessive assignment of salience to objects and events in the external environment. The close association between salient occurrences and increases in body temperature suggests that antipsychotic drugs may also reduce emotional hyperthermia. OBJECTIVES: We determined whether chlorpromazine, clozapine, and risperidone dose dependently reduce emotionally elicited increases in BAT thermogenesis, cutaneous vasoconstriction, and body temperature in rats. METHODS: Rats, chronically instrumented for measurement of BAT and body temperature and tail artery blood flow, singly housed, were confronted with an intruder rat (confined within a small wire-mesh cage) after systemic pre-treatment of the resident rat with vehicle or antipsychotic agent. BAT and body temperatures, tail blood flow, and behavioral activity were continuously measured. RESULTS: Clozapine (30 µg-2 mg/kg), chlorpromazine (0.1-5 mg/kg), and risperidone (6.25 µg-1 mg/kg) robustly and dose-relatedly reduced intruder-elicited BAT thermogenesis and tail artery vasoconstriction, with consequent dose-related reduction in emotional hyperthermia. CONCLUSIONS: Chlorpromazine, a first-generation antipsychotic, as well as clozapine and risperidone, second-generation agents, dose-dependently reduce emotional hyperthermia. Dopamine D2 receptor antagonist properties of chlorpromazine do not contribute to thermoregulatory effects. Interactions with monoamine receptors are important, and these monoamine receptor interactions may also contribute to the therapeutic effects of all three antipsychotics. Thermoregulatory actions of putative antipsychotic agents may constitute a biological marker of their therapeutic properties.

Biological predictors of insulin resistance associated with posttraumatic stress disorder in young military veterans.

Posttraumatic stress disorder (PTSD) is associated with increased risk for Type 2 diabetes and cardiovascular disease (cardiometabolic disease), warranting research into targeted prevention strategies. In the present case-control study of 160 young (mean age 32.7 years) male military veterans, we aimed to assess whether PTSD status predicted increased markers of cardiometabolic risk in otherwise healthy individuals, and further, to explore biological pathways between PTSD and these increased markers of cardiometabolic risk. Toward these aims, we compared measures of cardiometabolic risk, namely insulin resistance (IR) (HOMA-IR), metabolic syndrome (MetS) and prediabetes, between 80 PTSD cases and 80 controls without PTSD. We then determined whether PTSD-associated increases in HOMA-IR were correlated with select biological variables from pathways previously hypothesized to link PTSD with cardiometabolic risk, including systemic inflammation (increased C-reactive protein, interleukin-6, and tumor necrosis factor α), sympathetic over-activity (increased resting heart rate), and neuroendocrine dysregulation (increased plasma cortisol or serum brain-derived neurotrophic factor (BDNF)). We found PTSD diagnosis was associated with substantially higher HOMA-IR (cases 4.3±4.3 vs controls 2.4±2.0; p<0.001), and a higher frequency of MetS (cases 21.3% vs controls 2.5%; p<0.001), but not prediabetes (cases 20.0% vs controls 18.8%; p>0.05). Cases also had increased pro-inflammatory cytokines (p<0.01), heart rate (p<0.001), and BDNF (p<0.001), which together predicted increased HOMA-IR (adjusted R2=0.68, p<0.001). Results show PTSD diagnosis in young male military veterans without cardiometabolic disease is associated with increased IR, predicted by biological alterations previously hypothesized to link PTSD to increased cardiometabolic risk. Findings support further research into early, targeted prevention of cardiometabolic disease in individuals with PTSD.

Marijuana and other cannabinoids as a treatment for posttraumatic stress disorder: A literature review.

Posttraumatic stress disorder (PTSD) is common in the general population, yet there are limitations to the effectiveness, tolerability, and acceptability of available first-line interventions. We review the extant knowledge on the effects of marijuana and other cannabinoids on PTSD. Potential therapeutic effects of these agents may largely derive from actions on the endocannabinoid system and we review major animal and human findings in this area. Preclinical and clinical studies generally support the biological plausibility for cannabinoids' potential therapeutic effects, but underscore heterogeneity in outcomes depending on dose, chemotype, and individual variation. Treatment outcome studies of whole plant marijuana and related cannabinoids on PTSD are limited and not methodologically rigorous, precluding conclusions about their potential therapeutic effects. Reported benefits for nightmares and sleep (particularly with synthetic cannabinoid nabilone) substantiate larger controlled trials to determine effectiveness and tolerability. Of concern, marijuana use has been linked to adverse psychiatric outcomes, including conditions commonly comorbid with PTSD such as depression, anxiety, psychosis, and substance misuse. Available evidence is stronger for marijuana's harmful effects on the development of psychosis and substance misuse than for the development of depression and anxiety. Marijuana use is also associated with worse treatment outcomes in naturalistic studies, and with maladaptive coping styles that may maintain PTSD symptoms. Known risks of marijuana thus currently outweigh unknown benefits for PTSD. Although controlled research on marijuana and other cannabinoids' effects on PTSD remains limited, rapid shifts in the legal landscape may now enable such studies, potentially opening new avenues in PTSD treatment research.

MICA-A toolbox for masked independent component analysis of fMRI data.

Independent component analysis (ICA) is a widely used technique for investigating functional connectivity (fc) in functional magnetic resonance imaging data. Masked independent component analysis (mICA), that is, ICA restricted to a defined region of interest, has been shown to detect local fc networks in particular brain regions, including the cerebellum, brainstem, posterior cingulate cortex, operculo-insular cortex, hippocampus, and spinal cord. Here, we present the mICA toolbox, an open-source GUI toolbox based on FSL command line tools that performs mICA and related analyses in an integrated way. Functions include automated mask generation from atlases, essential preprocessing, mICA-based parcellation, back-reconstruction of whole-brain fc networks from local ones, and reproducibility analysis. Automated slice-wise calculation and cropping are additional functions that reduce computational time and memory requirements for large analyses. To validate our toolbox, we tested these different functions on the cerebellum, hippocampus, and brainstem, using resting-state and task-based data from the Human Connectome Project. In the cerebellum, mICA detected six local networks together with their whole-brain counterparts, closely replicating previous results. MICA-based parcellation of the hippocampus showed a longitudinally discrete configuration with greater heterogeneity in the anterior hippocampus, consistent with animal and human literature. Finally, brainstem mICA detected motor and sensory nuclei involved in the motor task of tongue movement, thereby replicating and extending earlier results. Hum Brain Mapp 37:3544-3556, 2016. © 2016 Wiley Periodicals, Inc.

A data-driven approach to mapping cortical and subcortical intrinsic functional connectivity along the longitudinal hippocampal axis.

The hippocampus (HPC) is functionally heterogeneous along the longitudinal anterior-posterior axis. In rodent models, gene expression maps define at least three discrete longitudinal subregions, which also differ in function, and in anatomical connectivity with the rest of the brain. In humans, equivalent HPC subregions are less well defined, resulting in a lack of consensus in neuroimaging approaches that limits translational study. This study determined whether a data-driven analysis, namely independent component analysis (ICA), could reproducibly define human HPC subregions, and map their respective intrinsic functional connectivity (iFC) with the rest of the brain. Specifically, we performed ICA of resting-state fMRI activity spatially restricted within the HPC, to determine the configuration and reproducibility of functional HPC components. Using dual regression, we then performed multivariate analysis of iFC between resulting HPC components and the whole brain, including detailed connectivity with the hypothalamus, a functionally important connection not yet characterized in human. We found hippocampal ICA resulted in highly reproducible longitudinally discrete components, with greater functional heterogeneity in the anterior HPC, consistent with animal models. Anterior hippocampal components shared iFC with the amygdala, nucleus accumbens, medial prefrontal cortex, posterior cingulate cortex, midline thalamus, and periventricular hypothalamus, whereas posterior hippocampal components shared iFC with the anterior cingulate cortex, retrosplenial cortex, and mammillary bodies. We show that spatially masked hippocampal ICA with dual regression reproducibly identifies functional subregions in the human HPC, and maps their respective brain intrinsic connectivity. Hum Brain Mapp 37:462-476, 2016. © 2015 Wiley Periodicals, Inc.

Cannabidiol as a Potential Treatment for Anxiety Disorders.

Cannabidiol (CBD), a Cannabis sativa constituent, is a pharmacologically broad-spectrum drug that in recent years has drawn increasing interest as a treatment for a range of neuropsychiatric disorders. The purpose of the current review is to determine CBD's potential as a treatment for anxiety-related disorders, by assessing evidence from preclinical, human experimental, clinical, and epidemiological studies. We found that existing preclinical evidence strongly supports CBD as a treatment for generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder, and post-traumatic stress disorder when administered acutely; however, few studies have investigated chronic CBD dosing. Likewise, evidence from human studies supports an anxiolytic role of CBD, but is currently limited to acute dosing, also with few studies in clinical populations. Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders, with need for further study of chronic and therapeutic effects in relevant clinical populations.

Heterogeneity in signaled active avoidance learning: substantive and methodological relevance of diversity in instrumental defensive responses to threat cues.

Individuals exposed to traumatic stressors follow divergent patterns including resilience and chronic stress. However, researchers utilizing animal models that examine learned or instrumental threat responses thought to have translational relevance for Posttraumatic Stress Disorder (PTSD) and resilience typically use central tendency statistics that assume population homogeneity. This approach potentially overlooks fundamental differences that can explain human diversity in response to traumatic stressors. The current study tests this assumption by identifying and replicating common heterogeneous patterns of response to signaled active avoidance (AA) training. In this paradigm, rats are trained to prevent an aversive outcome (shock) by performing a learned instrumental behavior (shuttling between chambers) during the presentation of a conditioned threat cue (tone). We test the hypothesis that heterogeneous trajectories of threat avoidance provide more accurate model fit compared to a single mean trajectory in two separate studies. Study 1 conducted 3 days of signaled AA training (n = 81 animals) and study 2 conducted 5 days of training (n = 186 animals). We found that four trajectories in both samples provided the strongest model fit. Identified populations included animals that acquired and retained avoidance behavior on the first day (Rapid Avoiders: 22 and 25%); those who never successfully acquired avoidance (Non-Avoiders; 20 and 16%); a modal class who acquired avoidance over 3 days (Modal Avoiders; 37 and 50%); and a population who demonstrated a slow pattern of avoidance, failed to fully acquire avoidance in study 1 and did acquire avoidance on days 4 and 5 in study 2 (Slow Avoiders; 22.0 and 9%). With the exception of the Slow Avoiders in Study 1, populations that acquired demonstrated rapid step-like increases leading to asymptotic levels of avoidance. These findings indicate that avoidance responses are heterogeneous in a way that may be informative for understanding both resilience and PTSD as well as the nature of instrumental behavior acquisition. Characterizing heterogeneous populations based on their response to threat cues would increase the accuracy and translatability of such models and potentially lead to new discoveries that explain diversity in instrumental defensive responses.

Transmission of colour and acuity signals by parvocellular cells in marmoset monkeys.

The red-green axis of colour vision evolved recently in primate evolutionary history. Signals serving red-green colour vision travel together with signals serving spatial vision, in the parvocellular (PC) division of the subcortical visual pathway. However, the question of whether receptive fields of PC pathway cells are specialized to transmit red-green colour signals remains unresolved. We addressed this question in single-cell recordings from the lateral geniculate nucleus of anaesthetized marmosets. Marmosets show a high proportion of dichromatic (red-green colour-blind) individuals, allowing spatial and colour tuning properties of PC cells to be directly compared in dichromatic and trichromatic visual systems. We measured spatial frequency tuning for sine gratings that provided selective stimulation of individual photoreceptor types. We found that in trichromatic marmosets, the foveal visual field representation is dominated by red-green colour-selective PC cells. Colour selectivity of PC cells is reduced at greater eccentricities, but cone inputs to centre and surround are biased to create more selectivity than predicted by a purely 'random wiring' model. Thus, one-to-one connections in the fovea are sufficient, but not necessary, to create colour-selective responses. The distribution of spatial tuning properties for achromatic stimuli shows almost complete overlap between PC cells recorded in dichromatic and trichromatic marmosets. These data indicate that transmission of red-green colour signals has been enabled by centre-surround receptive fields of PC cells, and has not altered the capacity of PC cells to serve high-acuity vision at high stimulus contrast.

Segregation of short-wavelength sensitive ("blue") cone signals among neurons in the lateral geniculate nucleus and striate cortex of marmosets.

We measured functional input from short-wavelength selective (S) cones to neurons in the dorsal lateral geniculate nucleus (LGN) and striate cortex (area V1) in anaesthetized marmosets. We found that most magnocellular (MC) and parvocellular (PC) cells receive very little (<5%) functional input from S cones, whereas blue-on cells of the koniocellular (KC) pathway receive dominant input from S cones. Cells dominated by S cone input were not encountered in V1, but V1 cells received more S cone input than PC or MC cells. This suggests that S cone inputs are distributed broadly among neurons in V1. No differences in strength of S cone inputs were seen on comparing dichromatic and trichromatic marmosets, suggesting that the addition of a medium-long wavelength selective cone-opponent ("red-green") channel to a dichromatic visual system does not detectably affect the chromatic properties of the S cone pathways.

Specificity of M and L cone inputs to receptive fields in the parvocellular pathway: random wiring with functional bias.

Many of the parvocellular pathway (PC) cells in primates show red-green spectral selectivity (cone opponency), but PC ganglion cells in the retina show no anatomical signs of cone selectivity. Here we asked whether responses of PC cells are compatible with "random wiring" of cone inputs. We measured long-wavelength-sensitive (L) and medium-wavelength-sensitive (M) cone inputs to PC receptive fields in the dorsal lateral geniculate of marmosets, using discrete stimuli (apertures and annuli) to achieve functional segregation of center and surround. Receptive fields between the fovea and 30 degrees eccentricity were measured. We show that, in opponent PC cells, the center is dominated by one (L or M) cone type, with normally <20% contribution from the other cone type (high "cone purity"), whereas non-opponent cells have mixed L and M cone inputs to the receptive field center. Furthermore, opponent response strength depends on the overall segregation of L and M cone inputs to center and surround rather than exclusive input from one cone type to either region. These data are consistent with random wiring. The majority of PC cells in both foveal (<8 degrees) and peripheral retina nevertheless show opponent responses. This arises because cone purity in the receptive field surround is at least as high as in the center, and the surround in nearly all opponent PC cells is dominated by the opposite cone type to that which dominates the center. These functional biases increase the proportion of opponent PC cells, but their anatomical basis is unclear.

Contribution of chromatic aberrations to color signals in the primate visual system.

We measured responses to red-green color variation in parvocellular (PC) neurons in the lateral geniculate nucleus of dichromatic ("red-green color blind") marmoset monkeys. Although these animals lack distinct visual pigments to distinguish between wavelengths in this range, many of the colored stimuli nevertheless produced robust responses in PC cells. We show that these responses, which are restricted to high stimulus spatial frequencies (fine image details), arise from chromatic aberrations in the eye. The neural signals produced by chromatic aberrations are of comparable magnitude to signals produced by high-frequency luminance (LUM) modulation and thus could influence cortical pathways for processing of color and object recognition. The fact that genetically "color-blind" primates are not necessarily blind to wavelength-dependent contours in the visual world may have enabled red-green color vision to become linked with high-acuity spatial vision during primate evolution.

Chromatic and spatial properties of parvocellular cells in the lateral geniculate nucleus of the marmoset (Callithrix jacchus).

The parvocellular (PC) division of the afferent visual pathway is considered to carry neuronal signals which underlie the red-green dimension of colour vision as well as high-resolution spatial vision. In order to understand the origin of these signals, and the way in which they are combined, the responses of PC cells in dichromatic ('red-green colour-blind') and trichromatic marmosets were compared. Visual stimuli included coloured and achromatic gratings, and spatially uniform red and green lights presented at varying temporal phases and frequencies.The sensitivity of PC cells to red-green chromatic modulation was found to depend primarily on the spectral separation between the medium- and long-wavelength-sensitive cone pigments (20 or 7 nm) in the two trichromatic marmoset phenotypes studied. The temporal frequency dependence of chromatic sensitivity was consistent with centre-surround interactions. Some evidence for chromatic selectivity was seen in peripheral PC cells. The receptive field dimensions of parvocellular cells were similar in dichromatic and trichromatic animals, but the achromatic contrast sensitivity of cells was slightly higher (by about 30%) in dichromats than in trichromats. These data support the hypothesis that the primary role of the PC is to transmit high-acuity spatial signals, with red-green opponent signals appearing as an additional response dimension in trichromatic animals.