Hyper-responsivity to losses in the anterior insula during economic choice scales with depression severity.

BACKGROUND: Commonly observed distortions in decision-making among patients with major depressive disorder (MDD) may emerge from impaired reward processing and cognitive biases toward negative events. There is substantial theoretical support for the hypothesis that MDD patients overweight potential losses compared with gains, though the neurobiological underpinnings of this bias are uncertain. METHODS: Twenty-one unmedicated patients with MDD were compared with 25 healthy controls (HC) using functional magnetic resonance imaging (fMRI) together with an economic decision-making task over mixed lotteries involving probabilistic gains and losses. Region-of-interest analyses evaluated neural signatures of gain and loss coding within a core network of brain areas known to be involved in valuation (anterior insula, caudate nucleus, ventromedial prefrontal cortex). RESULTS: Usable fMRI data were available for 19 MDD and 23 HC subjects. Anterior insula signal showed negative coding of losses (gain > loss) in HC subjects consistent with previous findings, whereas MDD subjects demonstrated significant reversals in these associations (loss > gain). Moreover, depression severity further enhanced the positive coding of losses in anterior insula, ventromedial prefrontal cortex, and caudate nucleus. The hyper-responsivity to losses displayed by the anterior insula of MDD patients was paralleled by a reduced influence of gain, but not loss, stake size on choice latencies. CONCLUSIONS: Patients with MDD demonstrate a significant shift from negative to positive coding of losses in the anterior insula, revealing the importance of this structure in value-based decision-making in the context of emotional disturbances.

The context of uncertainty modulates the subcortical response to predictability.

Implicit motor learning tasks typically involve comparisons of subject responses during a sequence versus a random condition. In neuroimaging, brain regions that are correlated with a sequence are described, but the temporal relationship of sequence versus nonsequence conditions is often not explored. We present a functional magnetic resonance imaging (fMRI) study describing activation related to sequential predictability in an implicit sensorimotor learning task and the history (context) dependence of these effects. Participants regarded four squares displayed horizontally across a screen and pressed a button when any one of the four targets was illuminated in a particular color. A repeating spatial sequence with varying levels of predictability was embedded within a random color presentation. Both the right dorsolateral prefrontal cortex (R DLPFC) and right caudate displayed a positive correlation to increasing predictability, whereas the left posterior parietal cortex (L PPC) displayed a negative correlation. However, the activation changes within the caudate were significant when transitioning from high predictability to low predictability but not for the reverse case, suggesting a sensitivity not only to predictability but to order effects as well. These results support the hypothesized relationship between basal ganglia and visuomotor sequential learning, but demonstrate the importance of context upon sequence learning.

Predictability modulates human brain response to reward.

Certain classes of stimuli, such as food and drugs, are highly effective in activating reward regions. We show in humans that activity in these regions can be modulated by the predictability of the sequenced delivery of two mildly pleasurable stimuli, orally delivered fruit juice and water. Using functional magnetic resonance imaging, the activity for rewarding stimuli in both the nucleus accumbens and medial orbitofrontal cortex was greatest when the stimuli were unpredictable. Moreover, the subjects' stated preference for either juice or water was not directly correlated with activity in reward regions but instead was correlated with activity in sensorimotor cortex. For pleasurable stimuli, these findings suggest that predictability modulates the response of human reward regions, and subjective preference can be dissociated from this response.

Conscious and unconscious processing of nonverbal predictability in Wernicke's area.

The association of nonverbal predictability and brain activation was examined using functional magnetic resonance imaging in humans. Participants regarded four squares displayed horizontally across a screen and counted the incidence of a particular color. A repeating spatial sequence with varying levels of predictability was embedded within a random color presentation. Both Wernicke's area and its right homolog displayed a negative correlation with temporal predictability, and this effect was independent of individuals' conscious awareness of the sequence. When individuals were made aware of the underlying sequential predictability, a widespread network of cortical regions displayed activity that correlated with the predictability. Conscious processing of predictability resulted in a positive correlation to activity in right prefrontal cortex but a negative correlation in posterior parietal cortex. These results suggest that conscious processing of predictability invokes a large-scale cortical network, but independently of awareness, Wernicke's area processes predictive events in time and may not be exclusively associated with language.

Continuous functional magnetic resonance imaging reveals dynamic nonlinearities of "dose-response" curves for finger opposition.

Linear experimental designs have dominated the field of functional neuroimaging, but although successful at mapping regions of relative brain activation, the technique assumes that both cognition and brain activation are linear processes. To test these assumptions, we performed a continuous functional magnetic resonance imaging (MRI) experiment of finger opposition. Subjects performed a visually paced bimanual finger-tapping task. The frequency of finger tapping was continuously varied between 1 and 5 Hz, without any rest blocks. After continuous acquisition of fMRI images, the task-related brain regions were identified with independent components analysis (ICA). When the time courses of the task-related components were plotted against tapping frequency, nonlinear "dose- response" curves were obtained for most subjects. Nonlinearities appeared in both the static and dynamic sense, with hysteresis being prominent in several subjects. The ICA decomposition also demonstrated the spatial dynamics with different components active at different times. These results suggest that the brain response to tapping frequency does not scale linearly, and that it is history-dependent even after accounting for the hemodynamic response function. This implies that finger tapping, as measured with fMRI, is a nonstationary process. When analyzed with a conventional general linear model, a strong correlation to tapping frequency was identified, but the spatiotemporal dynamics were not apparent.

Functional neuroimaging.

Functional neuroimaging represents an area of brain imaging that has undergone tremendous advancements in the last decade. It is now possible to design experiments that elucidate the functional interplay between brain regions that give rise to specific human cognitive processes. Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) form the core technologies that have allowed such studies. This article reviews the basis of these techniques, their strengths and limitations, the underlying neurophysiology, and the future of functional neuroimaging.

A computational model of how the basal ganglia produce sequences.

We propose a systems-level computational model of the basal ganglia based closely on known anatomy and physiology. First, we assume that the thalamic targets, which relay ascending information to cortical action and planning areas, are tonically inhibited by the basal ganglia. Second, we assume that the output stage of the basal ganglia, the internal segment of the globus pallidus (Gpi), selects a single action from several competing actions via lateral interactions. Third, we propose that a form of local working memory exists in the form of reciprocal connections between the external globus pallidus (Gpe) and the subthalamic nucleus (STN). As a test of the model, the system was trained to learn a sequence of states that required the context of previous actions. The striatum, which was assumed to represent a conjunction of cortical states, directly selected the action in the GP during training. The STN-to-GP connection strengths were modified by an associative learning rule and came to encode the sequence after 20 to 40 iterations through the sequence. Subsequently, the system automatically reproduced the sequence when cued to the first action. The behavior of the model was found to be sensitive to the ratio of the striatal-nigral learning rate to the STN-GP learning rate. Additionally, the degree of striatal inhibition of the globus pallidus had a significant influence on both learning and the ability to select an action. Low learning rates, which would be hypothesized to reflect low levels of dopamine, as in Parkinson's disease, led to slow acquisition of contextual information. However, this could be partially offset by modeling a lesion of the globus pallidus that resulted in an increase in the gain of the STN units. The parameter sensitivity of the model is discussed within the framework of existing behavioral and lesion data.

Brain regions responsive to novelty in the absence of awareness.

Brain regions responsive to novelty, without awareness, were mapped in humans by positron emission tomography. Participants performed a simple reaction-time task in which all stimuli were equally likely but, unknown to them, followed a complex sequence. Measures of behavioral performance indicated that participants learned the sequences even though they were unaware of the existence of any order. Once the participants were trained, a subtle and unperceived change in the nature of the sequence resulted in increased blood flow in a network comprising the left premotor area, left anterior cingulate, and right ventral striatum. Blood flow decreases were observed in the right dorsolateral prefrontal and parietal areas. The time course of these changes suggests that the ventral striatum is responsive to novel information, and the right prefrontal area is associated with the maintenance of contextual information, and both processes can occur without awareness.

Strain in the medial collateral ligament of the human knee under single and combined loads.

Strain within the medial collateral ligament (MCL) was measured in 13 human knee specimens to determine both the single and combined external loads most likely to cause injury. Using a load application system which allowed six degrees of freedom with flexion angle being fixed, both single loads of anterior/posterior force, medial/lateral force, varus/valgus torque, and internal/external axial torque and all pairs of these loads were applied at flexion angles of 0 degrees and 30 degrees. Liquid mercury strain gages were used to measure strain at four sites in the MCL. Two of the sites were the anterior fibers superior and inferior to the joint line and the other two were posterior of the two anterior sites. A factorial analysis revealed a significant interaction between the site experiencing the greatest strain and flexion angle. The posterior superior site experienced significantly greater strain at 0 degree flexion whereas strains was significantly greater at the anterior superior site at 30 degree flexion. Of the single moments, external axial was more damaging than valgus in that the strain developed at equivalent load was significantly greater. None of the moment-moment combinations was identified as being significantly more damaging. A similar result held for the force-moment combinations.

A correlational model for the development of disparity selectivity in visual cortex that depends on prenatal and postnatal phases.

Neurons in the visual cortex require correlated binocular activity during a critical period early in life to develop normal response properties. We present a model for how the disparity selectivity of cortical neurons might arise during development. The model is based on Hebbian mechanisms for plasticity at synapses between geniculocortical neurons and cortical cells. The model is driven by correlated activity in retinal ganglion cells within each eye before birth and additionally between eyes after birth. With no correlations present between the eyes, the cortical model developed only monocular cells. Adding a small amount of correlation between eyes at the beginning of development produced cortical neurons that were entirely binocular and tuned to zero disparity. However, if an initial phase of purely same-eye correlations was followed by a second phase of development that included correlations between eyes, the cortical model became populated with both monocular and binocular cells. Moreover, in the two-phase model, binocular cells tended to be selective for zero disparity, whereas the more monocular cells tended to have nonzero disparity. This relationship between ocular dominance and disparity has been observed in the visual cortex of the cat by other workers. Differences in the relative timing of the two developmental phases could account for the higher proportion of monocular cells found in the visual cortices of other animals.

Roofplasty requirements in vitro for different tibial hole placements in anterior cruciate ligament reconstruction.

In this study we sought both to quantify the forces that result in anterior cruciate ligament graft impingement and the amount of roofplasty necessary to prevent it. The perpendicular force of the intercondylar roof against an anterior cruciate ligament graft was measured in seven fresh-frozen cadaveric knees. Two tibial hole placements were evaluated: an anterior/eccentric hole (26.6% +/- 3.1% of the sagittal depth) and a customized hole aligned 4 to 5 mm posterior and parallel to the slope of the intercondylar roof in the extended knee (42.0% +/- 2.6% of the sagittal depth). A transducer that measured the contact force with the graft was implanted in the roof. An extensive roofplasty was performed so that the sensor would bear all of the roof force. Graft tension was also measured. Extension moments were applied to 20 N-m with a six degree of freedom load application system. Load cycles were repeated with the roof force sensor backed out in 0.8 mm increments. The sensor backout represented a corresponding amount of bone removal in a roofplasty. The flexion angle at roof-graft contact was consistently greater using the anterior tibial hole than the customized one. This held true for all increments of sensor backout. With the anterior hole, the roof sensor (no backout) contacted the graft at 12.8 degrees +/- 6.7 degrees of flexion, whereas the customized hole resulted in contact at 4.1 degrees +/- 4.2 degrees (P = 0.020).(ABSTRACT TRUNCATED AT 250 WORDS)

Strain in the anteromedial bundle of the anterior cruciate ligament under combination loading.

Strain within the anteromedial bundle (AMB) of the anterior cruciate ligament (ACL) was measured in 13 human knee specimens in order to determine the combination of external loads most likely to cause injury. Using a load application system that allowed 5 df with the flexion angle being fixed, pure loads of anterior/posterior force, medial/lateral force, varus/valgus torque, and internal/external axial torque were applied at three flexion angles: 0 degrees, 15 degrees, 30 degrees. Combined loads were applied in pairs at two flexion angles: 0 degrees and 30 degrees. Liquid mercury strain gauges were used to measure strain in the ACL. Anterior tibial force was the primary determinant of strain in the anteromedial bundle. This strain was significantly larger at 30 degrees flexion than at 0 degrees. The strain sensitivity of the AMB to medial force was approximately one-half that to pure anterior force. The effect of anterior and medial forces was additive when applied in combination. Neither pure axial torque nor pure varus/valgus torque was observed to strain significantly the AMB at any of the flexion angles investigated. However, valgus torque in combination with anterior force resulted in a significantly larger strain than pure anterior force. Internal axial torque in combination with anterior force also resulted in a larger strain than pure anterior force.

The accuracy of signal intensity measurements in magnetic resonance imaging as evaluated within the knee.

Quantitative signal intensity measurements are being utilized in both clinical and research magnetic resonance imaging protocols. This paper addresses three questions in quantitative MRI measurements as evaluated within the knee: 1) the accuracy of quantitative measurements; 2) improvement of accuracy by phantom normalization; and 3) the amount of signal change that is clinically significant. Seven normal subjects were imaged on three different days within a 1-wk period. Test-tube phantoms of manganous chloride (MnCl2) were imaged posterior to the knee and were used to normalize each image. The variation in signal intensity within the same subject averaged 20% for both the anterior cruciate ligament (ACL) and the posterior cruciate ligament (PCL). The phantom variation was approximately 18%. Signal intensity normalization by background subtraction, background division, phantom division, or a combination of subtraction and division did not significantly improve either the phantom variation or the ligament variation. Given that an individual ligament intensity will be measured with standard errors of +/- 20% of its value, we calculated the minimum increase in signal intensity to be considered abnormal relative to a normal ligament. A relative signal increase of 46% can be considered pathologic with 95% confidence. These findings emphasize that quantitative measurements must be carefully assessed when being applied in clinical settings.

Unimpinged and impinged anterior cruciate ligament grafts: MR signal intensity measurements.

Regionalized magnetic resonance (MR) signal intensities were quantitatively measured in impinged and unimpinged anterior cruciate ligament (ACL) grafts. Images were obtained with a 1.5-T imager, and signal intensity was measured in the proximal, middle, and distal thirds of the graft. In 15 unimpinged ACL grafts, the signal intensity remained low and did not vary during the 1st year of graft implantation (45 images). In contrast, 17 impinged ACL grafts showed an increase in signal intensity in the distal two-thirds of the graft that persisted 1-3 years after implantation (P less than .001). Unimpinged grafts were placed in tibial tunnels posterior and parallel to the slope of the intercondylar roof. Reconstructions with anterior tibial tunnels resulted in graft impingement that caused increases in graft signal intensity. This increase demonstrates a clear association between surgical technique and the subsequent MR appearance of the graft.

Implementation of a five degree of freedom automated system to determine knee flexibility in vitro.

This article describes an automated system designed to study the complete flexibility functions of the knee in vitro. The system allows five degrees of freedom with flexion angle being fixed, though adjustable from 0 to 45 deg. Loads corresponding to each of the five motions can be applied independently and in any combination. The effect of weight bearing on knee flexibility can also be studied by including axial force as one of the five loads. The relative motions are measured with LVDT's and RVDT's, and the loads are measured with strain gage transducers. The system is digitally controlled with a closed feedback loop, allowing for any combination of programmed loads. A control algorithm on an IBM PC/AT monitors the loads on each axis and continuously adjusts stepping motors to correctly follow programmed loads. The machine coordinate system corresponds to clinically accepted definitions of motion yet retains sequence independence for rotations. Results are presented demonstrating the repeatability of using a functional definition of axis placement to align the leg within the machine. Results are also presented demonstrating the utility of the full flexibility functions of the knee, notably in the determination of significant load interactions between anterior/posterior force and internal/external torque, and varus/valgus torque and internal/external torque.

Exposure (dose) tables for hematoporphyrin derivative photoradiation therapy.

Two sets of tables are presented that permit the rapid determination of (1) milliwatts per centimeter2 based upon known site diameter and power output from fiber optic and (2) time of exposure (minutes and seconds) based upon known site diameter and power output from fiber optic.

Computer-based tracking of living cells.

A computer-based tracing technique has been developed to follow the movement of living cells and keep them centered in the field of view of an optical microscope. With the use of an image-processing system, the video image of a cell can be sufficiently processed to allow computer-recognition of the cell boundaries. Determination of the location of the center of the cell enables comparison of successive cell positions and correction for any cell movement. In order to illustrate the versatility of this technique, patterns of movement were obtained of cancerous and non-cancerous cells in an effort to determine the difference in motility between the two cell types. After examination of the data gathered, it was found that there is no difference in the motility between the two cell types over 1-h periods.

Laser microsurgery in cell and developmental biology.

New applications of laser microbeam irradiation to cell and developmental biology include a new instrument with a tunable wavelength (217- to 800-nanometer) laser microbeam and a wide range of energies and exposure durations (down to 25 X 10(-12) second). Laser microbeams can be used for microirradiation of selected nucleolar genetic regions and for laser microdissection of mitotic and cytoplasmic organelles. They are also used to disrupt the developing neurosensory appendages of the cricket and the imaginal discs of Drosophila.