A probabilistic atlas of fiber crossings for variability reduction of anisotropy measures.

Diffusion imaging enables assessment of human brain white matter (WM) in vivo. WM microstructural integrity is routinely quantified via fractional anisotropy (FA). However, FA is also influenced by the number of differentially oriented fiber populations per voxel. To date, the precise statistical relationship between FA and fiber populations has not been characterized, complicating microstructural integrity assessment. Here, we used 630 state-of-the-art diffusion datasets from the Human Connectome Project, which allowed us to infer the number of fiber populations per voxel in a model-free fashion. Beyond the known impact on mean FA, variance of anisotropy distributions was drastically impacted, not only for FA, but also the more recent anisotropy indices generalized FA and multidimensional anisotropy. To ameliorate this bias, we introduce a probabilistic WM atlas delineating the number of distinctly oriented fiber populations per voxel. Our atlas shows that the majority of WM voxels features two differentially directed fiber populations (44.7%) rather than unidirectional fibers (32.9%) and identified WM regions with high numbers of crossing fibers, referred to as crossing pockets. Compartmentalizing anisotropy drastically reduced variance in group comparisons ranging from the whole brain to a few voxels in a single slice. In summary, we demonstrate a systematic effect of intra-voxel diffusion inhomogeneity on anisotropy. Moreover, we introduce a potential solution: The provided probabilistic WM atlas can easily be used with any given diffusion dataset to enhance the statistical robustness of anisotropy measures and increase their neurobiological utility.

Maintaining a cautious state of mind during a recognition test: a large-scale fMRI study.

Decision criterion is an important factor in recognition memory, determining the amount of evidence required to judge an item as previously encountered. For a typical recognition memory test involving the prior study of a set of items, a conservative criterion establishes a higher standard of evidence for recognition and designates fewer items as previously studied. In contrast, a liberal criterion establishes a lower standard of evidence and designates more items as previously studied. Therefore, the hit rate and the correct rejection rate on a recognition memory test can be affected by both the memory strength of the studied items and the criterion used to make that judgment. Yet most neuroimaging studies of the successful retrieval effect (a contrast between hits and correct rejections) fail to measure or consider decision criterion. The goal of the current fMRI study with ninety-five participants was to directly manipulate decision criteria on two tests of recognition memory by varying the likelihood of an item's prior occurrence. Our results indicate that regions of the lateral prefrontal and parietal cortex associated with successful retrieval are significantly more active when using conservative criteria than liberal criteria. Furthermore, our results reveal that activity in these regions associated with successful retrieval can be accounted for by individual differences in the conservativeness of the decision criterion above and beyond any differences in memory strength. These results expound on the role of cognitive control in recognition memory and the neural mechanisms that mediate this processing.

Local termination pattern analysis: a tool for comparing white matter morphology.

Disconnections between structures in the brain have long been hypothesized to be the mechanism behind numerous disease states and pathological behavioral phenotypes. Advances in diffusion weighted imaging (DWI) provide an opportunity to study white matter, and therefore brain connectivity, in great detail. DWI-based research assesses white matter at two different scales: voxelwise indexes of anisotropy such as fractional anisotropy (FA) are used to compare small units of tissue and network-based methods compare tractography-based models of whole-brain connectivity. We propose a method called local termination pattern analysis (LTPA) that considers information about both local and global brain connectivity simultaneously. LTPA itemizes the subset of streamlines that pass through a small set of white matter voxels. The "local termination pattern" is a vector defined by counts of these streamlines terminating in pairs of cortical regions. To assess the reliability of our method we applied LTPA exhaustively over white matter voxels to produce complete maps of local termination pattern similarity, based on diffusion spectrum imaging (DSI) data from 11 individuals in triplicate. Here we show that local termination patterns from an individual are highly reproducible across the entire brain. We discuss how LTPA can be deployed into a clinical database and used to characterize white matter morphology differences due to disease, developmental or genetic factors.

Pouring or chilling a bottle of wine: an fMRI study on the prospective planning of object-directed actions.

This fMRI study investigates the neural mechanisms supporting the retrieval of action semantics. A novel motor imagery task was used in which participants were required to imagine planning actions with a familiar object (e.g. a toothbrush) or with an unfamiliar object (e.g. a pair of pliers) based on either goal-related information (i.e. where to move the object) or grip-related information (i.e. how to grasp the object). Planning actions with unfamiliar compared to familiar objects was slower and was associated with increased activation in the bilateral superior parietal lobe, the right inferior parietal lobe and the right insula. The stronger activation in parietal areas for unfamiliar objects fits well with the idea that parietal areas are involved in motor imagery and suggests that this process takes more effort in the case of novel or unfamiliar actions. In contrast, the planning of familiar actions resulted in increased activation in the anterior prefrontal cortex, suggesting that subjects maintained a stronger goal-representation when planning actions with familiar compared to unfamiliar objects. These findings provide further insight into the neural structures that support action semantic knowledge for the functional use of real-world objects and suggest that action semantic knowledge is activated most readily when actions are planned in a goal-directed manner.

The neural basis of love as a subliminal prime: an event-related functional magnetic resonance imaging study.

Throughout the ages, love has been defined as a motivated and goal-directed mechanism with explicit and implicit mechanisms. Recent evidence demonstrated that the explicit representation of love recruits subcorticocortical pathways mediating reward, emotion, and motivation systems. However, the neural basis of the implicit (unconscious) representation of love remains unknown. To assess this question, we combined event-related functional magnetic resonance imaging (fMRI) with a behavioral subliminal priming paradigm embedded in a lexical decision task. In this task, the name of either a beloved partner, a neutral friend, or a passionate hobby was subliminally presented before a target stimulus (word, nonword, or blank), and participants were required to decide if the target was a word or not. Behavioral results showed that subliminal presentation of either a beloved's name (love prime) or a passion descriptor (passion prime) enhanced reaction times in a similar fashion. Subliminal presentation of a friend's name (friend prime) did not show any beneficial effects. Functional results showed that subliminal priming with a beloved's name (as opposed to either a friend's name or a passion descriptor) specifically recruited brain areas involved in abstract representations of others and the self, in addition to motivation circuits shared with other sources of passion. More precisely, love primes recruited the fusiform and angular gyri. Our findings suggest that love, as a subliminal prime, involves a specific neural network that surpasses a dopaminergic-motivation system.

Beyond grasping: representation of action in human anterior intraparietal sulcus.

The fronto-parietal network has been implicated in the processing of multisensory information for motor control. Recent methodological advances with both fMRI and TMS provide the opportunity to dissect the functionality of this extensive network in humans and may identify distinct contributions of local neural populations within this circuit that are not only related to motor planning, but to goal oriented behavior as a whole. Herein, we review and make parallels between experiments in monkeys and humans on a broad array of motor as well as non-motor tasks in order to characterize the specific contribution of a region in the parietal lobe, the anterior intraparietal sulcus (aIPS). The intent of this article is to review: (1) the historical perspectives on the parietal lobe, particularly the aIPS; (2) extend and update these perspectives based on recent empirical data; and (3) discuss the potential implications of the revised functionality of the aIPS in relationship to complex goal oriented behavior and social interaction. Our contention is that aIPS is a critical node within a network involved in the higher order dynamic control of action, including representation of intended action goals. These findings may be important not only for guiding the design of future experiments investigating related issues but may also have valuable utility in other fields, such social neuroscience and biomedical engineering.

Normalizing motor-related brain activity: subthalamic nucleus stimulation in Parkinson disease.

OBJECTIVE: To test whether therapeutic unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson disease (PD) leads to normalization in the pattern of brain activation during movement execution and control of movement extent. METHODS: Six patients with PD were imaged off medication by PET during performance of a visually guided tracking task with the DBS voltage programmed for therapeutic (effective) or subtherapeutic (ineffective) stimulation. Data from patients with PD during ineffective stimulation were compared with a group of 13 age-matched control subjects to identify sites with abnormal patterns of activation. Conjunction analysis was used to identify those areas in patients with PD where activity normalized when they were treated with effective stimulation. RESULTS: For movement execution, effective DBS caused an increase of activation in the supplementary motor area (SMA), superior parietal cortex, and cerebellum toward a more normal pattern. At rest, effective stimulation reduced overactivity of SMA. Therapeutic stimulation also induced reductions of movement related "overactivity" compared with healthy subjects in prefrontal, temporal lobe, and basal ganglia circuits, consistent with the notion that many areas are recruited to compensate for ineffective motor initiation. Normalization of activity related to the control of movement extent was associated with reductions of activity in primary motor cortex, SMA, and basal ganglia. CONCLUSIONS: Effective subthalamic nucleus stimulation leads to task-specific modifications with appropriate recruitment of motor areas as well as widespread, nonspecific reductions of compensatory or competing cortical activity.

The basal ganglia network mediates the planning of movement amplitude.

This study addresses the hypothesis that the basal ganglia (BG) are involved specifically in the planning of movement amplitude (or covariates). Although often advanced, based on observations that Parkinson's disease (PD) patients exhibit hypokinesia in the absence of significant directional errors, this hypothesis has been challenged by a recent alternative, that parkinsonian hypometria could be caused by dysfunction of on-line feedback loops. To re-evaluate this issue, we conducted two successive experiments. In the first experiment we assumed that if BG are involved in extent planning then PD patients (who exhibit a major dysfunction within the BG network) should exhibit a preserved ability to use a direction precue with respect to normals, but an impaired ability to use an amplitude precue. Results were compatible with this prediction. Because this evidence did not prove conclusively that the BG is involved in amplitude planning (functional deficits are not restricted to the BG network in PD), a second experiment was conducted using positron emission tomography (PET). We hypothesized that if the BG is important for planning movement amplitude, a task requiring increased amplitude planning should produce increased activation in the BG network. In agreement with this prediction, we observed enhanced activation of BG structures under a precue condition that emphasized extent planning in comparison with conditions that emphasized direction planning or no planning. Considered together, our results are consistent with the idea that BG is directly involved in the planning of movement amplitude or of factors that covary with that parameter.

Basal ganglia network mediates the control of movement amplitude.

In the present study we address the hypothesis that the basal ganglia are specifically involved in the planning of movement amplitude (or related covariates). This prediction has often been put forward based on the observation that Parkinson's disease (PD) patients exhibit hypokinesia. A close examination of the literature shows, however, that this commonly reported clinical symptom is not consistently echoed by experimental observations. When required to point to visual targets in the absence of vision of the moving limb, PD subjects exhibit various patterns of inaccuracy, including hypometria, hypermetria, systematic direction bias, or direction-dependent errors. They have even been shown to be as accurate as healthy, age-matched subjects. The main aim of the current study is to address the origin of these inconsistencies. To this end, we required nine patients presenting with advanced PD and 15 age-matched control subjects to perform planar reaching movements to visual targets. Eight targets were presented in equally spaced directions around a circle centered on the hand's starting location. Based on a previously validated parsing procedure, end-point errors were segmented into localization and planning errors. Localization errors refer to the existence of systematic biases in the estimation of the initial hand location. These biases can potentially transform a simple pattern of pure amplitude errors into a complex pattern involving both amplitude and direction errors. Results indicated that localization errors were different in the PD patients and the control subjects. This is not surprising knowing both that proprioception is altered in PD patients and that the ability to locate the hand at rest relies mainly on the proprioceptive sense, even when vision is available. Unlike normal subjects, localization errors in PD were idiosyncratic, lacking a consistent pattern across subjects. When the confounding effect of initial hand localization errors was canceled, we found that end-point errors were only due to the implementation of an underscaled movement gain (15%), without direction bias. Interestingly, the level of undershoot was found to increase with the severity of the disease (inferred from the Unified Parkinson's Disease Rating Scale, UPDRS, motor score). We also observed that movement variability was amplified (32%), but only along the main movement axis (extent variability). Direction variability was not significantly different in the patient population and the control group. When considered together, these results support the idea that the basal ganglia are specifically involved in the control of movement amplitude (or of some covariates). We propose that this structure participates in extent planning by modulating cortical activity and/or the tuning of the spinal interneuronal circuits.

Selective activation of a parietofrontal circuit during implicitly imagined prehension.

It is generally held that motor imagery is the internal simulation of movements involving one's own body in the absence of overt execution. Consistent with this hypothesis, results from numerous functional neuroimaging studies indicate that motor imagery activates a large variety of motor-related brain regions. However, it is unclear precisely which of these areas are involved in motor imagery per se as opposed to other planning processes that do not involve movement simulation. In an attempt to resolve this issue, we employed event-related fMRI to separate activations related to hand preparation-a task component that does not demand imagining movements-from grip selection-a component previously shown to require the internal simulation of reaching movements. Our results show that in contrast to preparation of overt actions, preparation of either hand for covert movement simulation activates a large network of motor-related areas located primarily within the left cerebral and right cerebellar hemispheres. By contrast, imagined grip selection activates a distinct parietofrontal circuit that includes the bilateral dorsal premotor cortex, contralateral intraparietal sulcus, and right superior parietal lobule. Because these areas are highly consistent with the frontoparietal reach circuit identified in monkeys, we conclude that motor imagery involves action-specific motor representations computed in parietofrontal circuits.

Functional anatomy of nonvisual feedback loops during reaching: a positron emission tomography study.

Reaching movements performed without vision of the moving limb are continuously monitored, during their execution, by feedback loops (designated nonvisual). In this study, we investigated the functional anatomy of these nonvisual loops using positron emission tomography (PET). Seven subjects had to "look at" (eye) or "look and point to" (eye-arm) visual targets whose location either remained stationary or changed undetectably during the ocular saccade (when vision is suppressed). Slightly changing the target location during gaze shift causes an increase in the amount of correction to be generated. Functional anatomy of nonvisual feedback loops was identified by comparing the reaching condition involving large corrections (jump) with the reaching condition involving small corrections (stationary), after subtracting the activations associated with saccadic movements and hand movement planning [(eye-arm-jumping minus eye-jumping) minus (eye-arm-stationary minus eye-stationary)]. Behavioral data confirmed that the subjects were both accurate at reaching to the stationary targets and able to update their movement smoothly and early in response to the target jump. PET difference images showed that these corrections were mediated by a restricted network involving the left posterior parietal cortex, the right anterior intermediate cerebellum, and the left primary motor cortex. These results are consistent with our knowledge of the functional properties of these areas and more generally with models emphasizing parietal-cerebellar circuits for processing a dynamic motor error signal.

Motor learning of compatible and incompatible visuomotor maps.

Brain imaging studies demonstrate increasing activity in limb motor areas during early motor skill learning, consistent with functional reorganization occurring at the motor output level. Nevertheless, behavioral studies reveal that visually guided skills can also be learned with respect to target location or possibly eye movements. The current experiments examined motor learning under compatible and incompatible perceptual/motor conditions to identify brain areas involved in different perceptual-motor transformations. Subjects tracked a continuously moving target with a joystick-controlled cursor. The target moved in a repeating sequence embedded within random movements to block sequence awareness. Psychophysical studies of behavioral transfer from incompatible (joystick and cursor moving in opposite directions) to compatible tracking established that incompatible learning was occurring with respect to target location. Positron emission tomography (PET) functional imaging of compatible learning identified increasing activity throughout the precentral gyrus, maximal in the arm area. Incompatible learning also led to increasing activity in the precentral gyrus, maximal in the putative frontal eye fields. When the incompatible task was switched to a compatible response and the previously learned sequence was reintroduced, there was an increase in arm motor cortex. The results show that learning-related increases of brain activity are dynamic, with recruitment of multiple motor output areas, contingent on task demands. Visually guided motor sequences can be linked to either oculomotor or arm motor areas. Rather than identifying changes of motor output maps, the data from imaging experiments may better reflect modulation of inputs to multiple motor areas.

Proprioception does not quickly drift during visual occlusion.

Several perceptual studies have shown that the ability to estimate the location of the arm degrades quickly during visual occlusion. To account for this effect, it has been suggested that proprioception drifts when not continuously calibrated by vision. In the present study, we re-evaluated this hypothesis by isolating the proprioceptive component of position sense (i.e., the subjects were forced to rely exclusively on proprioception to locate their hand, which was not the case in earlier studies). Three experiments were conducted. In experiment 1, subjects were required to estimate the location of their unseen right hand, at rest, using a visual spot controlled by the left hand through a joystick. Results showed that the mean accuracy was identical whether the localization task was performed immediately after the positioning of the hand or after a 10-s delay. In experiments 2 and 3, subjects were required to point, without vision of their limb, to visual targets. These two experiments relied on the demonstration that biases in the perception of the initial hand location induced systematic variations of the movement characteristics (initial direction, final accuracy, end-point variability). For these motor tasks, the subjects did not pay attention to the initial hand location, which removed the possible occurrence of confounding cognitive strategies. Results indicated that movement characteristics were, on average, not affected when a 15-s or 20-s delay was introduced between the positioning of the arm at the starting point and the presentation of the target. When considered together, our results suggest that proprioception does not quickly drift in the absence of visual information. The potential origin of the discrepancy between our results and earlier studies is discussed.

PET: activation of cerebral blood flow and glucose metabolism.

Functional brain mapping based on the PET CBF and glucose metabolic methods remains an exceptionally productive approach for localizing brain function. The imaging techniques are remarkably standardized, and localization remains stable with a variety of data analysis methods (140,141). The methods are suitable for identifying functional reorganization in the setting of neurodegeneration, stroke, trauma, and the effects of epilepsy on cognition.

Functional adaptation of reactive saccades in humans: a PET study.

It is known that the saccadic system shows adaptive changes when the command sent to the extraocular muscles is inappropriate. Despite an abundance of supportive psychophysical investigations, the neurophysiological substrate of this process is still debated. The present study addresses this issue using H2(15)O positron emission tomography (PET). We contrasted three conditions in which healthy human subjects were required to perform saccadic eye movements toward peripheral visual targets. Two conditions involved a modification of the target location during the course of the initial saccade, when there is suppression of visual perception. In the RAND condition, intra-saccadic target displacement was random from trial-to-trial, precluding any systematic modification of the primary saccade amplitude. In the ADAPT condition, intra-saccadic target displacement was uniform, causing adaptive modification of the primary saccade amplitude. In the third condition (stationary, STAT), the target remained at the same location during the entire trial. Difference images reflecting regional cerebral-blood-flow changes attributable to the process of saccadic adaptation (ADAPT minus RAND; ADAPT minus STAT) showed a selective activation in the oculomotor cerebellar vermis (OCV; lobules VI and VII). This finding is consistent with neurophysiological studies in monkeys. Additional analyses indicated that the cerebellar activation was not related to kinematic factors, and that the absence of significant activation within the frontal eye fields (FEF) or the superior colliculus (SC) did not represent a false negative inference. Besides the contribution of the OCV to saccadic adaptation, we also observed, in the RAND condition, that the saccade amplitude was significantly larger when the previous trial involved a forward jump than when the previous trial involved a backward jump. This observation indicates that saccade accuracy is constantly monitored on a trial-to-trial basis. Behavioral measurements and PET observations (RAND minus STAT) suggest that this single-trial control of saccade amplitude may be functionally distinct from the process of saccadic adaptation.

Alterations in the functional anatomy of working memory in adult attention deficit hyperactivity disorder.

OBJECTIVE: The authors used a functional neuroimaging study with a working memory probe to investigate the pathophysiology of attention deficit hyperactivity disorder (ADHD). Their goal was to compare regional cerebral blood flow (rCBF) changes related to working memory in adults with and without ADHD. METHOD: Using [(15)O]H(2)O positron emission tomography (PET) studies, the authors compared the sites of neural activation related to working memory in six adult men diagnosed with ADHD and six healthy men without ADHD who were matched in age and general intelligence. RESULTS: Task-related changes in rCBF in the men without ADHD were more prominent in the frontal and temporal regions, but rCBF changes in men with ADHD were more widespread and primarily located in the occipital regions. CONCLUSIONS: These data suggest the use of compensatory mental and neural strategies by subjects with ADHD in response to a disrupted ability to inhibit attention to nonrelevant stimuli and the use of internalized speech to guide behavior.

Involvement of visual cortex in tactile discrimination of orientation.

The primary sense modalities (vision, touch and so on) are generally thought of as distinct. However, visual imagery is implicated in the normal tactile perception of some object properties, such as orientation, shape and size. Furthermore, certain tactile tasks, such as discrimination of grating orientation and object recognition, are associated with activity in areas of visual cortex. Here we show that disrupting function of the occipital cortex using focal transcranial magnetic stimulation (TMS) interferes with the tactile discrimination of grating orientation. The specificity of this effect is illustrated by its time course and spatial restriction over the scalp, and by the failure of occipital TMS to affect either detection of an electrical stimulus applied to the fingerpad or tactile discrimination of grating texture. In contrast, TMS over the somatosensory cortex blocked discrimination of grating texture as well as orientation. We also report that, during tactile discrimination of grating orientation, an evoked potential is recorded over posterior scalp regions with a latency corresponding to the peak of the TMS interference effect (about 180 ms). The findings indicate that visual cortex is closely involved in tactile discrimination of orientation. To our knowledge, this is the first demonstration that visual cortical processing is necessary for normal tactile perception.

Imaging of locally recurrent and metastatic thyroid cancer with positron emission tomography.

Serum thyroglobulin and imaging have been routinely used in the evaluation of thyroid cancer patients suspected of having metastatic or recurrent disease. A more sensitive technique capable of identifying the sites of disease not detected by current imaging methods might improve overall management. The objective in this study was to demonstrate the feasibility of using positron emission tomography (PET) for the detection of recurrent thyroid cancer. Thirty patients with a history of either papillary/follicular or medullary thyroid cancer suspected of having locally recurrent or metastatic cancer on the basis of elevated or rising blood markers were evaluated with PET. Imaging studies were performed with the radiotracer [F-18] fluorodeoxyglucose (FDG). A retrospective review of other imaging results was performed and compared to the PET results. PET was able to identify locally recurrent or metastatic papillary/follicular disease in all 24 patients studied with elevated or rising thyroglobulin. Similar results were obtained in 6 patients with medullary cancer recurrences in the presence of elevated calcitonin. In cases where follow-up data was obtainable (17/24 papillary/follicular cancers and 4/6 medullary cancers), disease was confirmed either directly by surgery and/or indirectly through changes or persistence of laboratory findings. The results support the hypothesis that in the presence of elevated blood markers indicative of recurrent thyroid cancer, PET may prove valuable as an adjunctive imaging test for identifying disease and influencing management in cases where conventional imaging fails to detect suspected disease.