Reversible deactivation of motor cortex reveals that areas in parietal cortex are differentially dependent on motor cortex for the generation of movement.

Primates are characterized by specializations for manual manipulation, including expansion of posterior parietal cortex (PPC) and, in Catarrhines, evolution of a dexterous hand and opposable thumb. Previous studies examined functional interactions between motor cortex and PPC in New World monkeys and galagos, by inactivating M1 and evoking movements from PPC. These studies found that portions of PPC depend on M1 to generate movements. We now add a species that more closely resembles humans in hand morphology and PPC: macaques. Inactivating portions of M1 resulted in all evoked movements being reduced (28%) or completely abolished (72%) at the PPC sites tested (in areas 5L, PF, and PFG). Anterior parietal area 2 was similarly affected (26% reduced and 74% abolished) and area 1 was the least affected (12% no effect, 54% reduced, and 34% abolished). Unlike previous studies in New World monkeys and galagos, interactions between both nonanalogous (heterotopic) and analogous (homotopic) M1 and parietal movement domains were commonly found in most areas. These experiments demonstrate that there may be two parallel networks involved in motor control: a posterior parietal network dependent on M1 and a network that includes area 1 that is relatively independent of M1. Furthermore, it appears that the relative size and number of cortical fields in parietal cortex in different species correlates with homotopic and heterotopic effect prevalence. These functional differences in macaques could contribute to more numerous and varied muscle synergies across major muscle groups, supporting the expansion of the primate manual behavioral repertoire observed in Old World monkeys.NEW & NOTEWORTHY Motor cortex and anterior and posterior parietal cortex form a sensorimotor integration network. We tested the extent to which parietal areas could initiate movements independent of M1. Our findings support the contention that, although areas 2, 5L, PF, and PFG are highly dependent on M1 to produce movement, area 1 may constitute a parallel corticospinal pathway that can function somewhat independently of M1. A similar functional architecture may underlie dexterous tool use in humans.

Distributed Motor Control of Limb Movements in Rat Motor and Somatosensory Cortex: The Sensorimotor Amalgam Revisited.

Which areas of the neocortex are involved in the control of movement, and how is motor cortex organized across species? Recent studies using long-train intracortical microstimulation demonstrate that in addition to M1, movements can be elicited from somatosensory regions in multiple species. In the rat, M1 hindlimb and forelimb movement representations have long been thought to overlap with somatosensory representations of the hindlimb and forelimb in S1, forming a partial sensorimotor amalgam. Here we use long-train intracortical microstimulation to characterize the movements elicited across frontal and parietal cortex. We found that movements of the hindlimb, forelimb, and face can be elicited from both M1 and histologically defined S1 and that representations of limb movement types are different in these two areas. Stimulation of S1 generates retraction of the contralateral forelimb, while stimulation of M1 evokes forelimb elevation movements that are often bilateral, including a rostral region of digit grasping. Hindlimb movement representations include distinct regions of hip flexion and hindlimb retraction evoked from S1 and hip extension evoked from M1. Our data indicate that both S1 and M1 are involved in the generation of movement types exhibited during natural behavior. We draw on these results to reconsider how sensorimotor cortex evolved.

The Multiple Representations of Complex Digit Movements in Primary Motor Cortex Form the Building Blocks for Complex Grip Types in Capuchin Monkeys.

In the present study, we investigated motor cortex (M1) and a small portion of premotor and parietal cortex using intracortical microstimulation in anesthetized capuchin monkeys. Capuchins are the only New World monkeys that have evolved an opposable thumb and use tools in the wild. Like most Old World monkeys and humans, capuchin monkeys have highly dexterous hands. We surveyed a large extent of M1 and found that ~22% of all evoked movements in M1 involved the digits, and the majority of these consisted of finger flexions and extensions. Different subtypes of movements could be identified, including opposable movements of digits 1 and 2 (D1 and D2). Interestingly, the pattern of such movements varied between animals. In one case, movements involved the adduction of the medial surface of D1 toward the lateral surface of D2, whereas in the other case, the tips of D1 and D2 came in contact. Unlike other primates examined, we also found extensive representations of the prehensile foot and tail. We propose that the manual behavioral repertoire of capuchin monkeys, which includes the use of tools in the wild, is well represented within the motor cortex in the form of muscle synergies between different body parts that compose these larger, complex behaviors.SIGNIFICANCE STATEMENT The ability to use tools is a milestone in human evolution. Capuchin monkeys are one of the few non-human primates that use tools in the wild. The present study is the first detailed exploration of the motor cortex of these primates using long-train intracortical microstimulation. Within primary motor cortex, we evoked finger movements involving flexions and extensions of multiple digits, or of the first and second digits alone. Interestingly, flexion of tail and toes could also be evoked. Together, these results suggest that the functional organization of the motor cortex represents not just muscles of the body, but muscle synergies that form the building blocks of the complex behavioral repertoire of these animals.

Cortical projections to the superior colliculus in grey squirrels (Sciurus carolinensis).

The superior colliculus is an important midbrain structure involved with integrating information from varying sensory modalities and sending motor signals to produce orienting movements towards environmental stimuli. Because of this role, the superior colliculus receives a multitude of sensory inputs from a wide variety of subcortical and cortical structures. Proportionately, the superior colliculus of grey squirrels is among the largest in size of all studied mammals, suggesting the importance of this structure in the behavioural characteristics of grey squirrels. Yet, our understanding of the connections of the superior colliculus in grey squirrels is lacking, especially with respect to possible cortical influences. In this study, we placed anatomical tracer injections within the medial aspect of the superior colliculus of five grey squirrels (Sciurus carolinensis) and analysed the areal distribution of corticotectal projecting cells in flattened cortex. V1 projections to the superior colliculus were studied in two additional animals. Our results indicate that the superior colliculus receives cortical projections from visual, higher order somatosensory, and higher order auditory regions, as well as limbic, retrosplenial and anterior cingulate cortex. Few, if any, corticotectal projections originate from primary motor, primary somatosensory or parietal cortical regions. This distribution of inputs is similar to the distribution of inputs described in other rodents such as rats and mice, yet the lack of inputs from primary somatosensory and motor cortex is features of corticotectal inputs more similar to those observed in tree shrews and primates, possibly reflecting a behavioural shift from somatosensory (vibrissae) to visual navigation.

Representations of Fine Digit Movements in Posterior and Anterior Parietal Cortex Revealed Using Long-Train Intracortical Microstimulation in Macaque Monkeys.

The current investigation in macaque monkeys utilized long-train intracortical microstimulation to determine the extent of cortex from which movements could be evoked. Not only were movements evoked from motor areas (PMC and M1), but they were also evoked from posterior parietal (5, 7a, 7b) and anterior parietal areas (3b, 1, 2). Large representations of digit movements involving only the index finger (D2) and thumb (D1), were elicited from areas 1, 2, 7b, and M1. Other movements evoked from these regions were similar to ethologically relevant movements that have been described in other primates. These include combined forelimb and mouth movements and full hand grasps. However, many other movements were much more complex and could not be categorized into any of the previously described ethological categories. Movements involving specific digits, which mimic precision grips, are unique to macaques and have not been described in New World or prosimian primates. We propose that these multiple and expanded motor representations of the digits co-evolved with the emergence of the opposable thumb and alterations in grip type in some anthropoid lineages.

Intracortical Microstimulation Maps of Motor, Somatosensory, and Posterior Parietal Cortex in Tree Shrews (Tupaia belangeri) Reveal Complex Movement Representations.

Long-train intracortical microstimulation (LT-ICMS) is a popular method for studying the organization of motor and posterior parietal cortex (PPC) in mammals. In primates, LT-ICMS evokes both multijoint and multiple-body-part movements in primary motor, premotor, and PPC. In rodents, LT-ICMS evokes complex movements of a single limb in motor cortex. Unfortunately, very little is known about motor/PPC organization in other mammals. Tree shrews are closely related to both primates and rodents and could provide insights into the evolution of complex movement domains in primates. The present study investigated the extent of cortex in which movements could be evoked with ICMS and the characteristics of movements elicited using both short train (ST) and LT-ICMS in tree shrews. We demonstrate that LT-ICMS and ST-ICMS maps are similar, with the movements elicited with ST-ICMS being truncated versions of those elicited with LT-ICMS. In addition, LT-ICMS-evoked complex movements within motor cortex similar to those in rodents. More complex movements involving multiple body parts such as the hand and mouth were also elicited in motor cortex and PPC, as in primates. Our results suggest that complex movement networks present in PPC and motor cortex were present in mammals prior to the emergence of primates.

Vascular Graft Infection: Incidence and Potential Risk Factors.

PURPOSE: The purpose of this study was to identify factors that increase the risk of vascular graft infections (VGI) in patients following abdominal or lower extremity revascularization surgery. DESIGN: Retrospective, descriptive study. METHODS: We reviewed the electronic health records of 223 patients who had undergone abdominal or lower extremity revascularization procedures from July 2012 to November 2014, looking for factors associated with VGI. We reviewed 28 preoperative, intraoperative, and post-operative factors. Descriptive statistics (mean, range, and standard deviation) were used to describe the sample; χ was used to determine correlations between the risk factors and subsequent VGIs. The level of significance was determined at P = .05, with a confidence level of 95%. RESULTS: We identified 33 cases of VGIs for the 223 charts reviewed, yielding an incidence rate of 15%. Seventeen of the 33 patients with VGI (51.5%) were male. The average age of patients who experienced VGI was 60.9 years (standard deviation, 12.2 years, range, 29-81 years). Preoperative factors that were shown to show statistical significance for the development of VGI were sequential procedures (P = .003), diabetes mellitus (P = .002), hemoglobin A1c more than 7.0 (P = .0002), blood glucose more than 180 mg/dL (P = .0006), and lack of mobility (0.0097). Intraoperative factors associated with VGI were hemostatic agents applied to the surgical field intraoperatively (P = .003) and perioperative hypoxemia (P = .027). Postoperative factors associated with VGI were discharge from the hospital to skilled nursing facility or acute rehabilitation facility (P = .005) and unscheduled clinic visits (P = .008). CONCLUSION: We measured a 15% incidence of VGI and identified multiple pre-, intra-, and postoperative associated factors. Vigilance is required to prevent VGI and knowledge of specific risk factors is important.

Resolving the organization of the territory of the third visual area: a new proposal.

In primates, the cortex adjoining the rostral border of V2 has been variously interpreted as belonging to a single visual area, V3, with dorsal V3 (V3d) representing the lower visual quadrant and ventral V3 (V3v) representing the upper visual quadrant, V3d and V3v constituting separate, incomplete visual areas, V3d and ventral posterior (VP), or V3d being divided into several visual areas, including a dorsomedial (DM) visual area, a medial visual area (M), and dorsal extension of VP (or VLP). In our view, the evidence from V1 connections strongly supports the contention that V3v and V3d are parts of a single visual area, V3, and that DM is a separate visual area along the rostral border of V3d. In addition, the retinotopy revealed by V1 connection patterns, microelectrode mapping, optical imaging mapping, and functional magnetic resonance imaging (fmri) mapping indicates that much of the proposed territory of V3d corresponds to V3. Yet, other evidence from microelectrode mapping and anatomical connection patterns supports the possibility of an upper quadrant representation along the rostral border of the middle of dorsal V2 (V2d), interpreted as part of DM or DM plus DI, and along the midline end of V2d, interpreted as the visual area M. While the data supporting these different interpretations appear contradictory, they also seem, to some extent, valid. We suggest that V3d may have a gap in its middle, possibly representing part of the upper visual quadrant that is not part of DM. In addition, another visual area, M, is likely located at the DM tip of V3d. There is no evidence for a similar disruption of V3v. For the present, we favor continuing the traditional concept of V3 with the possible modification of a gap in V3d in at least some primates.

Reversible deactivation of higher-order posterior parietal areas. II. Alterations in response properties of neurons in areas 1 and 2.

The role that posterior parietal (PPC) and motor cortices play in modulating neural responses in somatosensory areas 1 and 2 was examined with reversible deactivation by transient cooling. Multiunit recordings from neurons in areas 1 and 2 were collected from six anesthetized adult monkeys (Macaca mulatta) before, during, and after reversible deactivation of areas 5L or 7b or motor cortex (M1/PM), while select locations on the hand and forelimb were stimulated. Response changes were quantified as increases and decreases to stimulus-driven activity relative to baseline and analyzed during three recording epochs: during deactivation ("cool") and at two time points after deactivation ("rewarm 1," "rewarm 2"). Although the type of response change observed was variable, for neurons at the recording sites tested >90% exhibited a significant change in response during cooling of 7b while cooling area 5L or M1/PM produced a change in 75% and 64% of sites, respectively. These results suggest that regions in the PPC, and to a lesser extent motor cortex, shape the response characteristics of neurons in areas 1 and 2 and that this kind of feedback modulation is necessary for normal somatosensory processing. Furthermore, this modulation appears to happen on a minute-by-minute basis and may serve as the substrate for phenomena such as somatosensory attention.

Reversible deactivation of higher-order posterior parietal areas. I. Alterations of receptive field characteristics in early stages of neocortical processing.

Somatosensory processing in the anesthetized macaque monkey was examined by reversibly deactivating posterior parietal areas 5L and 7b and motor/premotor cortex (M1/PM) with microfluidic thermal regulators developed by our laboratories. We examined changes in receptive field size and configuration for neurons in areas 1 and 2 that occurred during and after cooling deactivation. Together the deactivated fields and areas 1 and 2 form part of a network for reaching and grasping in human and nonhuman primates. Cooling area 7b had a dramatic effect on receptive field size for neurons in areas 1 and 2, while cooling area 5 had moderate effects and cooling M1/PM had little effect. Specifically, cooling discrete locations in 7b resulted in expansions of the receptive fields for neurons in areas 1 and 2 that were greater in magnitude and occurred in a higher proportion of sites than similar changes evoked by cooling the other fields. At some sites, the neural receptive field returned to the precooling configuration within 5-22 min of rewarming, but at other sites changes in receptive fields persisted. These results indicate that there are profound top-down influences on sensory processing of early cortical areas in the somatosensory cortex.

Clinical implications of preoperative echocardiographic findings on cardiovascular outcomes following vascular surgery: An observational trial.

INTRODUCTION: Peripheral artery disease and cardiac disease are often comorbid conditions. Echocardiography is a diagnostic tool that can be performed preoperatively to risk stratify patients by a functional cardiac test. We hypothesized that ventricular dysfunction and valvular lesions were associated with an increased incidence of expanded major adverse cardiac events (Expanded MACE). METHODS AND MATERIALS: Retrospective cohort study from 2011 to 2020 including all patients from a major academic center who had vascular surgery and an echocardiographic study within two years of the index procedure. RESULTS: 813 patients were included in the study; a majority had a history of smoking (86%), an ASA score of 3 (65%), and were male (68%). Carotid endarterectomy was the most common surgery (24%) and the least common surgery was open abdominal aortic aneurysm repair (5%). We found no significant association between the echocardiographic findings of left ventricular dysfunction, right ventricular dysfunction, or valvular lesions and the postoperative development of Expanded MACE. CONCLUSIONS: The preoperative echocardiographic findings of left ventricular dysfunction, right ventricular dysfunction and moderate to severe valvular lesions were not predictive of an increased incidence of postoperative Expanded MACE. We identified a significant association between RV dysfunction and post-operative dialysis that should be interpreted carefully due to the small number of outcomes. The transition from open to endovascular surgery and advances in perioperative management may have led to improved cardiovascular outcomes. TRIAL REGISTRATION: Trial Registration: NCT04836702 (clinicaltrials.gov). https://www.google.com/search?client=firefox-b-d&q=NCT04836702.

Coevolution of motor cortex and behavioral specializations associated with flight and echolocation in bats.

Bats have evolved behavioral specializations that are unique among mammals, including self-propelled flight and echolocation. However, areas of motor cortex that are critical in the generation and fine control of these unique behaviors have never been fully characterized in any bat species, despite the fact that bats compose ∼25% of extant mammalian species. Using intracortical microstimulation, we examined the organization of motor cortex in Egyptian fruit bats (Rousettus aegyptiacus), a species that has evolved a novel form of tongue-based echolocation.1,2 We found that movement representations include an enlarged tongue region containing discrete subregions devoted to generating distinct tongue movement types, consistent with their behavioral specialization generating active sonar using tongue clicks. This magnification of the tongue in motor cortex is comparable to the enlargement of somatosensory representations in species with sensory specializations.3-5 We also found a novel degree of coactivation between the forelimbs and hindlimbs, both of which are involved in altering the shape and tension of wing membranes during flight. Together, these findings suggest that the organization of motor cortex has coevolved with peripheral morphology in bats to support the unique motor demands of flight and echolocation.

Cellular scaling rules for primate spinal cords.

The spinal cord can be considered a major sensorimotor interface between the body and the brain. How does the spinal cord scale with body and brain mass, and how are its numbers of neurons related to the number of neurons in the brain across species of different body and brain sizes? Here we determine the cellular composition of the spinal cord in eight primate species and find that its number of neurons varies as a linear function of cord length, and accompanies body mass raised to an exponent close to 1/3. This relationship suggests that the extension, mass and number of neurons that compose the spinal cord are related to body length, rather than to body mass or surface. Moreover, we show that although brain mass increases linearly with cord mass, the number of neurons in the brain increases with the number of neurons in the spinal cord raised to the power of 1.7. This faster addition of neurons to the brain than to the spinal cord is consistent with current views on how larger brains add complexity to the processing of environmental and somatic information.

The Evolution of the Pulvinar Complex in Primates and Its Role in the Dorsal and Ventral Streams of Cortical Processing.

Current evidence supports the view that the visual pulvinar of primates consists of at least five nuclei, with two large nuclei, lateral pulvinar ventrolateral (PLvl) and central lateral nucleus of the inferior pulvinar (PIcl), contributing mainly to the ventral stream of cortical processing for perception, and three smaller nuclei, posterior nucleus of the inferior pulvinar (PIp), medial nucleus of the inferior pulvinar (PIm), and central medial nucleus of the inferior pulvinar (PIcm), projecting to dorsal stream visual areas for visually directed actions. In primates, both cortical streams are highly dependent on visual information distributed from primary visual cortex (V1). This area is so vital to vision that patients with V1 lesions are considered "cortically blind". When the V1 inputs to dorsal stream area middle temporal visual area (MT) are absent, other dorsal stream areas receive visual information relayed from the superior colliculus via PIp and PIcm, thereby preserving some dorsal stream functions, a phenomenon called "blind sight". Non-primate mammals do not have a dorsal stream area MT with V1 inputs, but superior colliculus inputs to temporal cortex can be more significant and more visual functions are preserved when V1 input is disrupted. The current review will discuss how the different visual streams, especially the dorsal stream, have changed during primate evolution and we propose which features are retained from the common ancestor of primates and their close relatives.

Manganese cumulative exposure and symptoms: a follow-up study of alloy workers.

Long-term exposure to manganese (Mn) particulates through inhalation can be neurotoxic, with deficits in neuromotor and cognitive domains. Mn-exposed individuals also report symptoms, including fatigue, mood changes, irritability, concentration difficulties, and sweating in the absence of physical effort. The long-term course of Mn-related symptoms after cessation of exposure has never been examined. Male workers from a Mn-alloy production plant participated in a study on nervous system functions (initial examination), and were followed-up 14 years after plant closure. The relation between self-reported symptoms and Mn cumulative exposure index (CEI) was examined among 71 Mn-alloy workers and 71 referents. Symptoms from the questionnaire were grouped into categories, and the reported frequency was compared between referents and Mn-alloy workers in each Mn CEI tertile using General Linear Models, controlling for age, education, and alcohol consumption. A gradual increase in symptoms frequency was observed for complaints related to hearing and movement control both at initial and follow-up examination, and fatigue and autonomic nervous system only at initial examination. In addition, an exposure-effect relation was apparent for symptoms related to memory, concentration and balance reported at both examinations, with Mn-workers in the highest CEI tertile reporting the highest level of symptomatology. Sleeping complaints were not associated with exposure to Mn, while musculoskeletal pain and muscular weakness were reported more often by Mn-workers than referents but were not clearly related to CEI. The findings suggest that former Mn-alloy workers continue to perceive symptoms many years after cessation of exposure. Despite the limitations of self-reported symptoms, subjective complaints are an important part of a health assessment since they relate directly to perceived health status and day-to-day functioning.

Gender differences in the effects of organochlorines, mercury, and lead on thyroid hormone levels in lakeside communities of Quebec (Canada).

Environmental chemicals can disrupt endocrine balance and in particular thyroid hormone (TH) homeostasis. However, studies differ with respect to thyroid profile changes and gender differences are rarely examined. This study investigated the THs, triodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH), in relation to serum organochlorines (OCs), bioindicators of mercury (Hg) and blood lead (Pb) in 211 freshwater fish consumers (124 men and 87 women) from two communities in Canada. Thyroid hormones were within the normal range and the bioindicators of exposure were low compared to other reports on fish consumers. Stratified analysis showed that for women, serum T3 concentrations were negatively related to serum concentrations of PCB 138, PCB 153, the non-coplanar congeners, Arochlor 1260, and SigmaPCB, as well as p,p'-DDE. No relations were observed between T4 and any of the chemicals measured, but TSH was negatively related to blood Pb. For men, serum T4 was inversely related to PCB 138, non-ortho-substituted (dioxin-like) PCBs and SigmaPCB. A significant positive relationship was observed between serum TSH and different PCB congeners (PCB 138, PCB 180, non-coplanar congeners, mono-ortho coplanar congeners, dioxin-like PCBs), as well as SigmaPCB. Serum TSH increased with hair and blood Hg concentrations and was highest among those in the highest 50th percentile for both Hg and dioxin-like PCB congeners compared to the others. No associations were observed for T3 in men. These findings suggest that even at low concentrations, these environmental contaminants can interfere with thyroid status and effects may differ by gender.

Ecosystem matters: fish consumption, mercury intake and exposure among fluvial lake fish-eaters.

Many studies use the number of fish meals as an estimate of Hg intake, although fish Hg concentrations, even within the same species, can greatly vary. Furthermore, most freshwater advisories only refer to local catch, while market fish advisories only focus on market fish, although both can contribute to Hg body burden. The present study, carried out in lakeside communities from 2 ecosystems in Quebec, Canada, sought to (i) estimate Hg intake from local freshwater sources, hunted waterfowl and market fish and seafood, and (ii) examine the relations between fish consumption, estimated Hg intake and biomarkers of exposure. A total of 238 adults (18-74 years), who had consumed local catch within the past three months, responded to an extensive interview-administered fish and waterfowl frequency questionnaire. Anthropometric measures were taken and a self-administered questionnaire was used to obtain socio-demographic information. Hg intake was estimated as microg Hg/kg body weight/day. Blood and hair samples were analyzed for Hg content. Results showed that persons from one ecosystem ate significantly more fish compared to those from the other (median: 52.1 g/day vs 38.9 g/day), but presented significantly lower concentrations of hair Hg (median: 448.0 ng/g vs 730.5 ng/g), blood organic Hg (median: 1.1 microg/L vs 3.4 microg/L) and inorganic Hg (median: 0.4 microg/L vs 0.8 microg/L). Median daily total Hg intake was 0.080 microg/kg bw/day for the former community and 0.141 microg/kg bw/day for the latter. Overall, 59.5% from the first ecosystem and 41.0% from the other, exceeded the US EPA RfD (0.1 microg/kg bw/day), while 13.2% and 6.0%, respectively, exceeded the Canadian tolerable daily intake (0.47 microg/kg bw/day) for adults. For the two groups, freshwater fish consumption frequency, but not total fish, was positively associated with bioindicators of Hg while estimated Hg intake from freshwater catch as well as from total fish consumption were positively related to Hg biomarkers. There was a positive relation between consumption and estimated Hg intake from freshwater fish and blood inorganic Hg. These findings indicate that the number of fish can be a poor surrogate for Hg exposure. The differences observed here for Hg intake and exposure reflect ecosystem disparities in fish diversity and Hg bioaccumulation. Studies and advisories need to consider Hg fish concentrations and fish-eating patterns in different ecosystems, as well as the contribution of market fish. The relation between fish consumption and inorganic Hg exposure, reported as well in other studies, needs to be further investigated.

Past occupational exposure to airborne manganese in a manganese alloy plant.

A retrospective exposure assessment of a group of manganese (Mn) alloy workers was performed in conjunction with a 2004 follow-up study, 14 years after cessation of exposure, to evaluate the long-term effects of occupational Mn exposure on neurobehavioral functions. The ferro- and silico-Mn alloy plant opened in 1973 and closed in 1991. The airborne total Mn (TMn) exposures for job groupings were established using personal sampling data from a 1991 industrial hygiene survey. Historical short-term total dust (TDust) data were used to estimate past TDust exposure for job groupings and plant areas. Relationships between Mn content and TDust from the 1991 survey, supported by sparse historical data, were used to estimate TMn content in the historical TDust data. Results showed past personal TDust exposure levels much higher than those found in 1991. Changes in TDust levels and corresponding TMn levels were a function of changes in ventilation, work practices, and operations, not of product (ferro- or silico-Mn). Relationships between TMn and respirable Mn (RMn) from area sampling in 1991 were used to estimate RMn exposure for the job groups. Work histories for 112 workers were developed from payroll records, questionnaires, and interviews and combined with Mn exposure estimates to develop cumulative exposure indices (CEIs). The TMn CEI ranged from 0.27 mg/m(3)x years to 100.24 mg/m(3)x years, with an AM of 24.40 mg/m(3)x years and a GM of 14.06 mg/m(3)x years. The RMn CEI had an AM of 2.95 mg/m(3)x years and a GM of 1.78 mg/m(3)x years with a range of 0.05-12.03 mg/m(3)x years. Overall average TMn exposure intensity, the TMn CEI divided by time worked in years for each worker, had an AM of 1.6 mg Mn/m(3), a GM of 1.0 mg Mn/m(3), range 0.02-6.2 6 mg Mn/m(3). The results of the 2004 follow-up study showed several concentration-response relationships between TMn CEI and neurobehavioral outcomes, which suggest that increase in cumulative TMn exposure level has long-term consequences on the nervous system.