Integrating visual and tactile information in the perirhinal cortex.

By virtue of its widespread afferent projections, perirhinal cortex is thought to bind polymodal information into abstract object-level representations. Consistent with this proposal, deficits in cross-modal integration have been reported after perirhinal lesions in nonhuman primates. It is therefore surprising that imaging studies of humans have not observed perirhinal activation during visual-tactile object matching. Critically, however, these studies did not differentiate between congruent and incongruent trials. This is important because successful integration can only occur when polymodal information indicates a single object (congruent) rather than different objects (incongruent). We scanned neurologically intact individuals using functional magnetic resonance imaging (fMRI) while they matched shapes. We found higher perirhinal activation bilaterally for cross-modal (visual-tactile) than unimodal (visual-visual or tactile-tactile) matching, but only when visual and tactile attributes were congruent. Our results demonstrate that the human perirhinal cortex is involved in cross-modal, visual-tactile, integration and, thus, indicate a functional homology between human and monkey perirhinal cortices.

Physiological effects of nonthyroidal illness syndrome in patients after cardiac surgery.

In a prospective randomized placebo-controlled study, we assessed potential physiological effects of nonthyroidal illness syndrome (NTIS) in acute illness. Coronary artery bypass graft surgery was employed as a prospective model of acute illness and NTIS. Triiodothyronine (T(3)) or placebo was infused for 24 h after surgery, with a T(3) dose selected to maintain postoperative serum T(3) concentrations at preoperative levels. Patients were evaluated before coronary artery bypass graft and during the postoperative period. Cardiovascular function was monitored with Swan-Ganz catheter measurements and ECG. Urinary nitrogen excretion and L-[1-(13)C]leucine flux were used to evaluate protein metabolism. Serum measurements of relevant hormones, iron, and total iron-binding capacity were used to assess effects on sex steroid, growth hormone axis, and iron responses to illness. Cardiovascular function was not affected by T(3) infusion, except for a transient higher cardiac index in the T(3) group 6 h after surgery (3.04 +/- 0.12 for T(3) and 2.53 +/- 0.08 for placebo, P = 0.0016). Protein metabolism was not affected; changes in urinary nitrogen excretion and L-[1-(13)C]leucine flux were equivalent in the two groups (P = 0.35 and P = 0.95, respectively). No differences were observed in changes in testosterone, estrogens, growth hormone, insulin-like growth hormone I, iron, or total iron-binding capacity between T(3) and placebo groups. We conclude that, in the early stages of major illness, the decrease in circulating T(3) concentrations in NTIS has only a minimal transient physiological impact on cardiac function and plays no significant role in protecting against protein catabolism or modulating other endocrine responses or iron responses to illness.

Language control in the bilingual brain.

How does the bilingual brain distinguish and control which language is in use? Previous functional imaging experiments have not been able to answer this question because proficient bilinguals activate the same brain regions irrespective of the language being tested. Here, we reveal that neuronal responses within the left caudate are sensitive to changes in the language or the meaning of words. By demonstrating this effect in populations of German-English and Japanese-English bilinguals, we suggest that the left caudate plays a universal role in monitoring and controlling the language in use.

Reliable identification of the auditory thalamus using multi-modal structural analyses.

The medial geniculate body (MGB) of the thalamus is a key component of the auditory system. It is involved in relaying and transforming auditory information to the cortex and in top-down modulation of processing in the midbrain, brainstem, and ear. Functional imaging investigations of this region in humans, however, have been limited by the difficulty of distinguishing MGB from other thalamic nuclei. Here, we introduce two methods for reliably delineating MGB anatomically in individuals based on conventional and diffusion MRI data. The first uses high-resolution proton density weighted scanning optimized for subcortical grey-white contrast. The second uses diffusion-weighted imaging and probabilistic tractography to automatically segment the medial and lateral geniculate nuclei from surrounding structures based on their distinctive patterns of connectivity to the rest of the brain. Both methods produce highly replicable results that are consistent with published atlases. Importantly, both methods rely on commonly available imaging sequences and standard hardware, a significant advantage over previously described approaches. In addition to providing useful approaches for identifying the MGB and LGN in vivo, our study offers further validation of diffusion tractography for the parcellation of grey matter regions on the basis of their connectivity patterns.

How reading differs from object naming at the neuronal level.

This paper uses whole brain functional neuroimaging in neurologically normal participants to explore how reading aloud differs from object naming in terms of neuronal implementation. In the first experiment, we directly compared brain activation during reading aloud and object naming. This revealed greater activation for reading in bilateral premotor, left posterior superior temporal and precuneus regions. In a second experiment, we segregated the object-naming system into object recognition and speech production areas by factorially manipulating the presence or absence of objects (pictures of objects or their meaningless scrambled counterparts) with the presence or absence of speech production (vocal vs. finger press responses). This demonstrated that the areas associated with speech production (object naming and repetitively saying "OK" to meaningless scrambled pictures) corresponded exactly to the areas where responses were higher for reading aloud than object naming in Experiment 1. Collectively the results suggest that, relative to object naming, reading increases the demands on shared speech production processes. At a cognitive level, enhanced activation for reading in speech production areas may reflect the multiple and competing phonological codes that are generated from the sublexical parts of written words. At a neuronal level, it may reflect differences in the speed with which different areas are activated and integrate with one another.

The left parietal and premotor cortices: motor attention and selection.

It is well established that the premotor cortex has a central role in the selection of movements. The role of parts of the parietal cortex in movement control has proved more difficult to describe but appears to be related to the preparation and the redirection of movements and movement intentions. We have referred to some of these processes as motor attention. It has been known since the time of William James that covert motor attention can be directed to an upcoming movement just as visuospatial attention can be directed to a location in space. While some parietal regions, particularly in the right hemisphere, are concerned with covert orienting and the redirecting of covert orienting it may be useful to consider other parietal regions, in the anterior inferior parietal lobule and in the posterior superior parietal lobule, particularly in the left hemisphere, as contributing to motor attention. Such parts of the parietal lobe are activated in neuroimaging experiments when subjects covertly prepare movements or switch intended movements. Lesions or transcranial magnetic stimulation (TMS) affect the redirecting of motor attention. The difficulties apraxic patients experience when sequencing movements may partly be due to an inability to redirect motor attention from one movement to another. The role of the premotor cortex in selecting movements is also lateralized to the left hemisphere. Damage to left hemisphere movement selection mechanisms may also contribute to apraxia. If, however, it remains intact after a stroke then the premotor cortex may contribute to the recovery of arm movements. A group of patients with unilateral left hemisphere lesions and impaired movements in the contralateral right hand was studied. Functional magnetic resonance imaging showed that in some cases the premotor cortex in the intact hemisphere was more active when the stroke-affected hand was used. TMS in the same area in the same patients had the most disruptive effect on movements. In summary, patterns of motor impairment and recovery seen after strokes can partly be explained with reference to the roles of the parietal and premotor cortices in motor attention and selection.

Towards understanding language organisation in the brain using fMRI.

Functional magnetic resonance imaging (fMRI), which allows non-invasive mapping of human cognitive functions, has become an important tool for understanding language function. An understanding of component processes and sources of noise in the images is contributing to increased confidence in the reproductability of studies. This allows clinical applications, e.g., for pre-surgical lateralisation of language functions in patients with temporal lobe epilepsy. fMRI is a sensitive method for mapping regions involved in language functions. We recently have applied it to study the effect of word surface form on reading with a comparison of responses to Chinese characters or alphabetical Pinyin. Interpretation of fMRI activations must be made with caution; fMRI suggests task-associated activation, but does not independently confirm that such activity is necessary. However, complementary studies can be performed using transcranial magnetic stimulation (TMS), which can be used to interfere with brain activity in a specific region transiently for characterisation of the behavioural effects. We describe how TMS combined with fMRI has confirmed a role for the left inferior frontal cortex in semantic processing.

How is the fusiform gyrus related to category-specificity?

There is growing evidence from functional imaging studies that distinct regions in the fusiform gyri are differentially sensitive to object category. In this paper, we investigate how the areas that are more sensitive to animals than tools respond to other visual and semantic variables. We illustrate that (1) category effects in the fusiform areas are stronger for pictures of objects than their written names; (2) retrieving information on the colour or size of objects activates a left lateralised fusiform area that lies anterior to the category-sensitive areas; and (3) both left and right category-sensitive areas respond strongly to visual feature detection on false fonts-meaningless visual stimuli with no semantic associations. These results dissociate the responses in two fusiform areas: The posterior category-sensitive areas are primarily modulated by visual input, whereas a more anterior polymodal region is involved in the retrieval of visual information. In addition, we demonstrate that the posterior areas which are more active for animals than tools are also more active for fruits than tools. Our data are therefore consistent with the proposal that activation in the lateral posterior fusiform gyri reflects the demands on structural differentiation. Since animals and fruits tend to have more structurally similar neighbours than man-made kinds of objects, category effects are likely to be observed during most picture identification tasks. In contrast, when the stimuli are written or auditory names, category effects may only be observed when the task requires access to fine spatial details in the objects' structures.

Anatomic constraints on cognitive theories of category specificity.

Many cognitive theories of semantic organization stem from reports of patients with selective, category-specific deficits for particular classes of objects (e.g., fruit). The anatomical assumptions underlying the competing claims can be evaluated with functional neuroimaging but the findings to date have been inconsistent and insignificant when standard statistical criteria are adopted. We hypothesized that category differences in functional brain responses might be small and task dependent. To test this hypothesis, we entered data from seven PET studies into a single multifactorial design which crossed category (living vs man-made) with a range of tasks. Reliable category-specific effects were observed but only for word retrieval and semantic decision tasks. Living things activated medial aspects of the anterior temporal poles bilaterally while tools activated a left posterior middle temporal region. These category-by-task interactions provide robust evidence for an anatomical double dissociation according to category and place strong constraints on cognitive theories of the semantic system. Furthermore they reconcile some of the apparent inconsistencies between lesion studies and functional neuroimaging data.

Susceptibility-induced loss of signal: comparing PET and fMRI on a semantic task.

Functional magnetic resonance imaging (fMRI) has become a popular tool for investigations into the neural correlates of cognitive activity. One limitation of fMRI, however, is that it has difficulty imaging regions near tissue interfaces due to distortions from macroscopic susceptibility effects which become more severe at higher magnetic field strengths. This difficulty can be particularly problematic for language tasks that engage regions of the temporal lobes near the air-filled sinuses. This paper investigates susceptibility-induced signal loss in the temporal lobes and proposes that by defining a priori regions of interest and using the small-volume statistical correction of K. J. Worsley, S. Marrett, P. Neelin, A. C. Vandal, K. J. Friston, and A. C. Evans (1996, Hum. Brain Mapp. 4: 58-83), activations in these areas can sometimes be detected by increasing the statistical power of the analysis. We conducted two experiments, one with PET and the other with fMRI, using almost identical semantic categorization paradigms and comparable methods of analysis. There were areas of overlap as well as differences between the PET and fMRI results. One anticipated difference was a lack of activation in two regions in the temporal lobe on initial analyses in the fMRI data set. With a specific region of interest, however, activation in one of the regions was detected. These experiments demonstrate three points: first, even for almost identical cognitive tasks such as those in this study, PET and fMRI may not produce identical results; second, differences between the two methods due to macroscopic susceptibility artifacts in fMRI can be overcome with appropriate statistical corrections, but only partially; and third, new data acquisition paradigms are necessary to fully deal with susceptibility-induced signal loss if the sensitivity of the fMRI experiment to temporal lobe activations is to be enhanced.

Category-specific semantic deficits in focal and widespread brain damage: a computational account.

Category-specific semantic impairments have been explained in terms of preferential damage to different types of features (e.g., perceptual vs. functional). This account is compatible with cases in which the impairments were the result of relatively focal lesions, as in herpes encephalitis. Recently, however, there have been reports of category-specific impairments associated with Alzheimer's disease, in which there is more widespread, patchy damage. We present experiments with a connectionist model that show how "category-specific" impairments can arise in cases of both localized and widespread damage; in this model, types of features are topographically organized, but specific categories are not. These effects mainly depend on differences between categories in the distribution of correlated features. The model's predictions about degree of impairment on natural kinds and artifacts over the course of semantic deterioration are shown to be consistent with existing patient data. The model shows how the probabilistic nature of damage in Alzheimer's disease interacts with the structure of semantic memory to yield different patterns of impairment between patients and categories over time.

Double dissociation of semantic categories in Alzheimer's disease.

Data that demonstrate distinct patterns of semantic impairment in Alzheimer's disease (AD) are presented. Findings suggest that while groups of mild-moderate patients may not display category specific impairments, some individual patients do show selective impairment of either natural kinds or artifacts. We present a model of semantic organization in which category specific impairments arise from damage to distributed features underlying different types of categories. We incorporate the crucial notions of intercorrelations and distinguishing features, allowing us to demonstrate (1) how category specific impairments can result from widespread damage and (2) how selective deficits in AD reflect different points in the progression of impairment. The different patterns of impairment arise from an interaction between the nature of the semantic categories and the progression of damage.

Effects of dietary protein restriction on regional amino acid metabolism in insulin-dependent diabetes mellitus.

We studied subjects with insulin-dependent diabetes mellitus (IDDM) and controls by administering primed continuous infusions of L-[1-13C,15N)]leucine and L-[2,3-13C2]alanine to measure whole body and forearm metabolism of these amino acids during ample protein intake and again after 4 wk of moderately restricted protein intake. Decreased rates of whole body protein degradation, leucine transamination, leucine oxidation, and increased forearm alanine release produced by dietary protein restriction occurred equivalently in IDDM subjects under short-term tightly managed glycemia and in controls. Dietary protein restriction did not affect whole body alanine appearance or forearm leucine appearance, disposal, or balance in IDDM subjects or controls. IDDM subjects differed from controls only in that normal forearm leucine balance was maintained at higher rates of leucine appearance and disposal. We conclude that IDDM subjects adapt normally to dietary protein restriction. Undernutrition during moderate protein deprivation in these patients likely occurs during episodes of poor glycemic control.

Decreased protein catabolism after exercise in subjects with IDDM.

We examined whether the increased rates of protein catabolism (proteolysis and leucine oxidation) associated with moderate insulinopenia in subjects with IDDM would be accentuated by prior bicycle exercise (53% VO2max for 82 min). Insulin infusions maintained plasma glucose concentrations on one study day in "tight" control (TC: 6 mmol/l) and on a separate day in "loose" control (LC: 12 mmol/l). Elevations in serum ketone body, plasma NEFA, and whole-blood branched-chain amino acid concentrations on the loose control day during the basal period persisted throughout the post-exercise recovery period. Amino acid kinetics were estimated during a primed, constant infusion of L-[1-13C]leucine from plasma dilution of alpha-[1-13C]KIC and expired air 13CO2 enrichments. Loose control was associated with increased rates of whole-body leucine oxidation (LC 25 +/- 7 vs TC 21 +/- 8 mumol.kg-1.h-1) and protein degradation (LC 127 +/- 12 vs TC 118 +/- 18 mumol.kg-1.h-1) (both p < 0.05). During the 2-h post exercise recovery period, there were significant decreases in rates of leucine oxidation (LC 21 +/- 7, TC 16 +/- 7) and protein degradation (LC 112 +/- 13, TC 107 +/- 11), compared to the basal period (both p < 0.05, basal vs recovery). Rates of whole-body protein synthesis were unchanged by prior exercise. In conclusion, moderate insulinopenia is associated with significantly higher rates of protein degradation and leucine oxidation in the basal state. Following exercise, net protein catabolism is diminished due to reduced rates of protein degradation in the presence of maintained rates of protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of exercise on insulin sensitivity in humans.

Physical exercise is promoted as one of the primary therapeutic strategies available to increase insulin sensitivity in individuals deemed at risk from insulin resistance and its attendant hyperinsulinism. Subjects with non-insulin-dependent diabetes mellitus (NIDDM) and impaired glucose tolerance (IGT) represent the major clinical population in which physical training is promoted as a treatment modality to improve insulin sensitivity. This manuscript reviews both the acute effects of muscular contractions and the effects of physical training on insulin sensitivity in NIDDM and insulin-dependent diabetic (IDDM) human subjects. Additionally, the effects of localized (regional) muscular contractions on insulin-mediated glucose disposal in previously exercised and nonexercised muscle groups will be discussed briefly.

Effects of low-protein diets on protein metabolism in insulin-dependent diabetes mellitus patients with early nephropathy.

The dietary protein requirements of patients with insulin-dependent diabetes mellitus (IDDM) are unknown. We studied the metabolic adaptation of IDDM patients with early nephropathy to therapeutic, low-protein diets. Six patients were studied at baseline and following 1 and 12 weeks of consuming 0.6 g/kg-1 ideal body weight.day-1 protein. Outcome variables included quadriceps muscle strength, body composition, nitrogen balance, and estimates of whole body protein turnover using an infusion of L-[1-13C]leucine. All subjects experienced decreased muscle strength (6.6% decline in maximal torque, P = 0.05) and increased body fatness (11% increase in fat mass, P = 0.03) with no change in total body weight. This was accompanied by an initial 40% decrease in the rate of whole-body leucine oxidation after 1 week of dietary restriction which returned almost to baseline rates by 12 weeks (P less than 0.001, 1 week vs. 12 weeks). Nitrogen balance remained negative throughout the period of protein restriction. We conclude that IDDM subjects with early nephropathy experience protein undernutrition during the first 3 months of the dietary protein restriction currently recommended for the treatment of nephropathy. This may result, in part, from an inability to conserve essential amino acids from oxidative loss over the time period of the study.

Effect of obesity on plasma insulin-like growth factor-I in cancer patients.

Starvation and malnutrition are associated with low concentrations of plasma insulin-like growth factor I (IGF-I). To evaluate the utility of IGF-I as a screening test for malnutrition, we compared plasma IGF-I concentrations with anthropometric measurements of nutritional status in 99 cancer patients. Forty-three percent of patients were overweight and 4 percent were underweight. Log IGF-I correlated negatively with body weight (r = -0.31, P = 0.002), midarm muscle area (MAMA) (r = -0.31, P = 0.001), triceps skinfold thickness (TSF) (r = -0.24, P = 0.03) and body mass index (r = -0.31, P = 0.003). In males plasma IGF-I correlated with TSF but not MAMA; in females IGF-I correlated with MAMA but not TSF, suggestive of a sexual dimorphism between plasma IGF-I and indices of adiposity. We conclude that obesity was far more prevalent than undernutrition, and that plasma IGF-I correlated negatively with indices of adiposity in a gender specific fashion. Because IGF-I is significantly reduced in the obese as well as in the malnourished, measurements of plasma IGF-I are unlikely to be of adequate clinical specificity to serve as a useful screening test for subtle alterations in nutritional status.

Pre-exercise feeding does not affect endurance cycle exercise but attenuates post-exercise starvation-like response.

The effects of ingesting a mixed-snack food (CB), fructose (FRU), or placebo (PBO) prior to exercise (70% peak VO2) on the metabolic response during and after cycle exercise were studied in eight normal healthy volunteers with a wide range of peak VO2 (30-70 cc.kg-1.min-1). The study was designed to minimize the impact of confounding factors by using various strategies. First, the volunteers were grouped in teams with stratification by peak VO2, and the tests were randomized by a Latin-square design. Second, subjects received two acclimation trials in the cycle ergometer to diminish the effect of learning experiences and allow them to get used to the room and equipment. In addition, financial incentives were offered for team and individual endurance times. The test meals were administered 30 min prior to the beginning of exercise, and the subjects exercised to exhaustion, which was defined with clear-cut endpoints. Gas and blood samples were taken at regular intervals before, during, and for 60 min after each exercise bout. CB and FRU induced higher pre-exercise glucose and insulin concentrations. Blood lactate increased 100% with FRU ingestion. Despite these differences; endurance time, substrate, and hormone concentrations as well as rates of substrate oxidation during exercise were identical among the three conditions. During the post-exercise recovery period, PBO was associated with a starvation-like pattern of substrate utilization in which lipid oxidation was 60% greater and carbohydrate oxidation 50% less than following either CB (75 +/- 11, 248 +/- 27 mg.min-1, P less than 0.05) or F ingestion (93 +/- 4, 221 +/- 14 mg.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of treadmill exercise on fuel metabolism in hepatic cirrhosis.

We studied whole body and regional fuel metabolism before, during, and after 90 min of treadmill exercise at 50% of maximal aerobic capacity (VO2max) in four subjects with hepatic cirrhosis and in four normal volunteers. Rates of endogenous glucose production (EGP) were measured using D-[6-3H]glucose infusions and fuel oxidation using indirect calorimetry. In the basal state, cirrhotic subjects had similar rates of EGP compared with controls. Forearm release of alanine and lactate was significantly greater in cirrhotic subjects (P less than 0.05), suggesting increased basal rates of gluconeogenesis. During exercise, EGP increased 2- to 2.5-fold in control subjects (P less than 0.01) but did not increase in cirrhotic subjects. Despite lower glucose concentrations in cirrhotic subjects, progressive hypoglycemia did not occur during exercise, probably because cirrhotic subjects demonstrated increased plasma concentrations of fat-derived substrates and derived a greater percentage of total energy requirement from fat oxidation than did controls (P less than 0.05) and because forearm muscle glucose extraction was significantly lower in cirrhotic subjects compared with controls (0.5 vs. 3.6%, respectively; P less than 0.05). During recovery, control subjects demonstrated significant increases in EGP rates compared with both the basal and exercise periods, but cirrhotic subjects showed no increase. In conclusion, cirrhotic subjects failed to demonstrate the normal increase in EGP during and after exercise. Significant hypoglycemia during exercise did not occur, possibly because of the increased availability of fat-derived fuels, which may spare the requirement for circulating glucose as an oxidative fuel for exercising muscle tissues.