Shifted inferior frontal laterality in women with major depressive disorder is related to emotion-processing deficits.

BACKGROUND: Facial emotion perception (FEP) is a critical human skill for successful social interaction, and a substantial body of literature suggests that explicit FEP is disrupted in major depressive disorder (MDD). Prior research suggests that weakness in FEP may be an important phenomenon underlying patterns of emotion-processing challenges in MDD and the disproportionate frequency of MDD in women. Method Women with (n = 24) and without (n = 22) MDD, equivalent in age and education, completed a FEP task during functional magnetic resonance imaging. RESULTS: The MDD group exhibited greater extents of frontal, parietal and subcortical activation compared with the control group during FEP. Activation in the inferior frontal gyrus (IFG) appeared shifted from a left >right pattern observed in healthy women to a bilateral pattern in MDD women. The ratio of left to right suprathreshold IFG voxels in healthy controls was nearly 3:1, whereas in the MDD group, there was a greater percentage of suprathreshold IFG voxels bilaterally, with no leftward bias. In MDD, relatively greater activation in right IFG compared with left IFG (ratio score) was present and predicted FEP accuracy (r = 0.56, p < 0.004), with an inverse relationship observed between FEP and subgenual cingulate activation (r = - 0.46, p = 0.02). CONCLUSIONS: This study links, for the first time, disrupted IFG activation laterality and increased subgenual cingulate activation with deficient FEP in women with MDD, providing an avenue for imaging-to-assessment translational applications in MDD.

Age differences in symbolic representations of motor sequence learning.

We recently reported that young adults (YA) preferentially recruit cerebellar lobule HVI for symbolic motor sequence learning [3]. Learning magnitude in the symbolic condition was correlated with activation level in lobule HVI. Here, we evaluated age differences in the symbolic representation of motor sequence learning. Fourteen YA and 14 older adults (OA) performed the alternating serial reaction time task (ASRT) under conditions in which the spatial processing component was selectively eliminated from stimulus presentation (spatial versus symbolic), response execution (manual versus vocal), or both. Results showed that OA had reduced learning magnitudes relative to YA. Using the cerebellum lobule HVI as a region-of-interest, we found that OA had significantly lower activation in this region than YA during the symbolic learning conditions (FWE, P<0.05). Similar to YA, OA also showed a significant correlation between learning magnitude and cerebellar activation in the symbolic conditions. These results suggest that although YA and OA recruit similar neural networks during implicit learning, OA under-recruit relevant brain areas which may partially explain their implicit sequence learning deficits.

Magnetic Resonance Imaging Estimation of Longitudinal Relaxation Rate Change (ΔR1) in Dual Gradient Echo Sequences Using an Adaptive Model.

Magnetic Resonance Imaging (MRI) estimation of contrast agent concentration in fast pulse sequences such as Dual Gradient Echo (DGE) imaging is challenging. An Adaptive Neural Network (ANN) was trained with a map of contrast agent concentration estimated by Look-Locker (LL) technique (modified version of inversion recovery imaging) as a gold standard. Using a set of features extracted from DGE MRI data, an ANN was trained to create a voxel based estimator of the time trace of CA concentration. The ANN was trained and tested with the DGE and LL information of six Fisher rats using a K-Fold Cross-Validation (KFCV) method with 60 folds and 10500 samples. The Area Under the Receiver Operator Characteristic Curve (AUROC) for 60 folds was used for training, testing and optimization of the ANN. After training and optimization, the optimal ANN (4:7:5:1) produced maps of CA concentration which were highly correlated (r =0.89, P < 0.0001) with the CA concentration estimated by the LL technique. The estimation made by the ANN had an excellent overall performance (AUROC = 0.870).

Symbolic representations in motor sequence learning.

It has been shown that varying the spatial versus symbolic nature of stimulus presentation and response production, which affects stimulus-response (S-R) mapping requirements, influences the magnitude of implicit sequence learning (Koch and Hoffman, 2000). Here, we evaluated how spatial and symbolic stimuli and responses affect the neural bases of sequence learning. We selectively eliminated the spatial component of stimulus presentation (spatial vs. symbolic), response execution (manual vs. vocal), or both. Fourteen participants performed the alternating serial reaction time task under these conditions in an MRI scanner, with interleaved acquisition to allow for recording of vocal response reaction times. Nine regions of interest (ROIs) were selected to test the hypothesis that the dorsolateral prefrontal cortex (DLPFC) was preferentially engaged for spatially cued conditions and cerebellum lobule HVI, crus I and II were associated with symbolically cued learning. We found that the left cerebellum lobule HVI was selectively recruited for symbolic learning and the percent signal change in this region was correlated with learning magnitude under the symbolic conditions. In contrast, the DLPFC did not exhibit selective activation for learning under spatial conditions. The inferior parietal lobule exhibited increased activation during learning regardless of the condition, supporting its role in forming an abstract representation of learned sequences. These findings reveal different brain networks that are flexibly engaged depending on the conditions of sequence learning.

Neuroanatomical correlates of motor acquisition and motor transfer.

The acquisition of new motor skills is dependent on task practice. In the case of motor transfer, learning can be facilitated by prior practice of a similar skill. Although a multitude of studies have investigated the brain regions contributing to skill acquisition, the neural bases associated with the savings seen at transfer have yet to be determined. In the current study, we used functional MRI to examine how brain activation differs during acquisition and transfer of a visuomotor adaptation task. Two groups of participants adapted manual aiming movements to three different rotations of the feedback display in a sequential fashion, with a return to baseline display conditions between each rotation. Subjects showed a savings in the rate of adaptation when they had prior adaptive experiences (i.e., positive transfer of learning). This savings was associated with a reduction in activity of brain regions typically recruited early in the adaptation process, including the right inferior frontal gyrus, primary motor cortex, inferior temporal gyrus, and the cerebellum (medial HIII). Moreover, although these regions exhibit activation that is correlated across subjects with the rate of acquisition, the degree of savings at transfer was correlated with activity in the right cingulate gyrus, left superior parietal lobule, right inferior parietal lobule, left middle occipital gyrus, and bilaterally in the cerebellum (HV/VI). The cerebellar activation was in the regions surrounding the posterior superior fissure, which is thought to be the site of storage for acquired internal models. Thus we found that motor transfer is associated with brain activation that typically characterizes late learning and storage. Transfer seems to involve retrieval of a previously formed motor memory, allowing the learner to move more quickly through the early stage of learning.

Bilateral basal ganglia activation associated with sensorimotor adaptation.

Sensorimotor adaptation tasks can be classified into two types. When subjects adapt movements to visual feedback perturbations such as in prism lens adaptation, they perform kinematic adaptations. When subjects adapt movements to force field perturbations such as with robotic manipulanda, they perform kinetic adaptations. Neuroimaging studies have shown basal ganglia involvement in kinetic adaptations, but have found little evidence of basal ganglia involvement in kinematic adaptations, despite reports of deficits in patients with diseases of the basal ganglia, such as Parkinson's and Huntington's disease, in these. In an effort to resolve such apparent discrepancy, we used FMRI to focus on the first few minutes of practice during kinematic adaptation. Human subjects adapted to visuomotor rotations in the context of a joystick aiming task while lying supine in a 3.0 T MRI scanner. As demonstrated previously, early adaptive processes were associated with BOLD activation in the cerebellum and the sensory and motor cortical regions. A novel finding of this study was bilateral basal ganglia activation. This suggests that, at least for early learning, the neural correlates of kinematic adaptation parallel those of other types of skill learning. We observed activation in the right globus pallidus and putamen, along with the right prefrontal, premotor and parietal cortex, which may support spatial cognitive processes of adaptation. We also observed activation in the left globus pallidus and caudate nucleus, along with the left premotor and supplementary motor cortex, which may support the sensorimotor processes of adaptation. These results are the first to demonstrate a clear involvement of basal ganglia activation in this type of kinematic motor adaptation.

Working memory for order and the parietal cortex: an event-related functional magnetic resonance imaging study.

Memory for order information has been tied to the frontal lobes, however, parietal activation is observed in many functional neuroimaging studies. Here we report functional magnetic resonance findings from an event-related experiment involving working memory for order. Five letters were presented for storage, followed after a delay by two probe items. Probe items could be separated by zero to three positions in the memory set and subjects had to indicate whether the items were in the correct order. Analyses indicate that activation in left parietal cortex shows a systematic decrease in activation with increasing probe distance. This finding is consistent with an earlier study in which we suggested that parietal cortical regions mediate the representation of order information via magnitude codes.

Feedforward and feedback processes in motor control.

In this study, we utilized functional magnetic resonance imaging (fMRI) to examine which brain regions contribute to feedback and feedforward motor control processes. Several studies have investigated the contributions of cortical and subcortical brain regions to motor performance by independently varying factors such as movement rate, force, and speed, and observing the neural responses. Such studies have contributed greatly to our understanding of neural coding of movement variables. Under natural movement conditions, however, these factors interact in a complex manner to produce differing performance levels. In the current investigation, we induced performance changes in a less constrained way, by having subjects move a joystick to hit targets of differing sizes on an LCD screen. These parametric changes in target size resulted in the well-known speed-accuracy tradeoff effect, allowing us to examine the brain regions responsive to global shifts in motor performance levels. That is, movements made to larger targets relied more on feedforward control whereas movements made to smaller targets relied more on feedback control. Using functional MRI, we identified two sets of brain regions in which activation was modulated with task difficulty. Areas exhibiting activation that was positively correlated with increasing target size included primary motor cortex, premotor cortex, and the basal ganglia, regions that are typically classified as playing a role in force control and movement planning. Brain regions whose activation was negatively correlated with increasing target size included the ipsilateral sensorimotor cortex, multiple cerebellar regions, and the thalamus. These areas contributed to motor performance under higher levels of task difficulty. The results elucidate cortical and subcortical brain regions that are responsive to global shifts in motor performance, reflecting changes along the continuum of feedforward and feedback motor control.

T(2)(*) dependence of low frequency functional connectivity.

Resting state low frequency (<0.08 Hz) fluctuations in MR timecourses that are temporally correlated between functionally related areas have been observed in recent studies. These fluctuations have been assumed to arise from spontaneous blood oxygenation level-dependent (BOLD) oscillations. This work examines the T(2)(*) characteristics of the low frequency fluctuations (functional connectivity) and compares them to those of task activation induced signal changes. Multi-echo spiral data were fit using a mono-exponential decay model to generate T(2)(*) and intensity (I(0)) parameter timecourses. Resultant correlation maps show that both functional connectivity and BOLD activation modulate T(2)(*), not I(0). Regression analysis also finds that both have a linear dependence on echo time. Thus, functional connectivity and task activation MR signal changes appear to arise from the same BOLD-related origins.

Cerebellar hemispheric activation ipsilateral to the paretic hand correlates with functional recovery after stroke.

An experimental lesion in the primary motor or sensory cortices in monkeys leads to functional reorganization in areas surrounding the lesion or in contralateral homologous regions. In humans, task-dependent brain activation after motor stroke seems to be multifocal and bilateral. Although many active structures are seen after stroke, their roles are unclear. For instance, the uninjured primary motor cortex may play a significant role in recovery or may be associated with mirror movements. Other motor areas, particularly those outside the affected middle cerebral artery distribution, have also been thought to play such a role, including the medial pre-motor areas and both cerebellar hemispheres. The lateral pre-motor areas might also contribute but the demarcation of primary motor and pre-motor cortices is not trivial. It is not known from existing studies how brain activation relates to behavioural change over the time course of recovery. We used functional MRI (fMRI) to study 12 patients longitudinally over the first 6 months of stroke recovery. All subjects had acute stroke causing unilateral arm weakness and had some ability to move the impaired hand within 1 month. Each patient had both motor testing and fMRI during finger and wrist movements at four points during the observed period. Six of these patients showed good motor recovery, whereas the other six did not. The imaging results support a role for the cerebellum in mediating functional recovery from stroke. The data suggest that patients with good recovery have clear changes in the activation of the cerebellar hemisphere opposite the injured corticospinal tract. Patients with poor recovery do not show such changes in cerebellar activation. No other brain region had a significant correlation with recovery. Interestingly, activation in the cerebellum ipsilateral to the injury increases transiently after stroke, independently of the success of recovery. The present work suggests a possible link between cerebellar activation and behavioural recovery from hand weakness from stroke. The underlying mechanism is not known, but it could relate to haemodynamic changes such as diaschisis or to the postulated role of the cerebellum in motor skill learning.

Lateralization of motor circuits and handedness during finger movements.

Although functional lateralization in the human brain has been studied intensively, there remains significant controversy over the brain mechanisms that instantiate it. The main objective of the present study is to characterize the regions associated with the generation of different movements by the fingers of both hands by right- and left-handed people. Thirteen right- and left-handers were studied using blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) during performance of single and sequential finger movement tasks. We used single-shot whole-brain spiral fMRI to map the functional components of the motor system during these tasks. Regions of interest included the primary motor and sensory cortices, the pre-motor cortices and the cerebellum. Sequential movements were associated with intense brain activation in several bilateral regions, whereas single movements were associated with less activation in fewer regions, but with greater laterality. Right- and left-handers differed in their pattern of activation, sharing a pattern of activation on simple movements but responding differently to sequential movements. On simple movements, the brain activation patterns of left- and right-handers were similar in volume, number of areas and laterality. By contrast, on sequential movement, left-handers activated larger volumes and a larger number of brain areas than right-handers, and showed significantly less brain lateralization. These results highlight differences in the functional organization of motor areas in right- and left-handed people. The discrepancies that might reflect differences in the network features of motor systems in these two groups, could also determine differences in motor activity that occur during recovery from injury (e.g. after stroke).

Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia.

OBJECTIVE: The dorsolateral prefrontal cortex has been implicated in both working memory and the pathophysiology of schizophrenia. A relationship among dorsolateral prefrontal cortex activity, working memory dysfunction, and symptoms in schizophrenia has not been firmly established, partly because of generalized cognitive impairments in patients and task complexity. Using tasks that parametrically manipulated working memory load, the authors tested three hypotheses: 1) patients with schizophrenia differ in prefrontal activity only when behavioral performance differentiates them from healthy comparison subjects, 2) dorsolateral prefrontal cortex dysfunction is associated with poorer task performance, and 3) dorsolateral prefrontal cortex dysfunction is associated with cognitive disorganization but not negative or positive symptoms. METHOD: Seventeen conventionally medicated patients with schizophrenia and 16 healthy comparison subjects underwent functional magnetic resonance imaging while performing multiple levels of the "n-back" sequential-letter working memory task. RESULTS: Patients with schizophrenia showed a deficit in physiological activation of the right dorsolateral prefrontal cortex (Brodmann's area 46/9) in the context of normal task-dependent activity in other regions, but only under the condition that distinguished them from comparison subjects on task performance. Patients with greater dorsolateral prefrontal cortex dysfunction performed more poorly. Dorsolateral prefrontal cortex dysfunction was selectively associated with disorganization symptoms. CONCLUSIONS: These results are consistent with the hypotheses that working memory dysfunction in patients with schizophrenia is caused by a disturbance of the dorsolateral prefrontal cortex and that this disturbance is selectively associated with cognitive disorganization. Further, the pattern of behavioral performance suggests that dorsolateral prefrontal cortex dysfunction does not reflect a deficit in the maintenance of stimulus representations per se but points to deficits in more associative components of working memory.

Sensitivity of prefrontal cortex to changes in target probability: a functional MRI study.

Electrophysiological studies suggest sensitivity of the prefrontal cortex to changes in the probability of an event. The purpose of this study was to determine if subregions of the prefrontal cortex respond differentially to changes in target probabilities using functional magnetic resonance imaging (fMRI). Ten right-handed adults were scanned using a gradient-echo, echo planar imaging sequence during performance of an oddball paradigm. Subjects were instructed to respond to any letter but "X". The frequency of targets (i.e., any letter but X) varied across trials. The results showed that dorsal prefrontal regions were active during infrequent events and ventral prefrontal regions were active during frequent events. Further, we observed an inverse relation between the dorsal and ventral prefrontal regions such that when activity in dorsal prefrontal regions increased, activity in ventral prefrontal regions decreased, and vice versa. This finding may index competing cognitive processes or capacity limitations. Most importantly, these findings taken as a whole suggest that any simple theory of prefrontal cortex function must take into account the sensitivity of this region to changes in target probability.

Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia.

BACKGROUND: Previously we proposed that dorsolateral prefrontal cortex (PFC) supports a specific working memory (WM) subcomponent: the ability to represent and maintain context information necessary to guide appropriate task behavior. By context, we mean prior task-relevant information represented in such a form that it supports selection of the appropriate behavioral response. Furthermore, we hypothesized that WM deficits in schizophrenia reflect impaired context processing due to a disturbance in dorsolateral PFC. We use functional magnetic resonance imaging to examine PFC activation in medication-naive, first-episode patients with schizophrenia during a WM, task-isolating context processing. METHODS: Fourteen first-episode, medication-naive patients with schizophrenia and 12 controls similar in age, sex, and parental education underwent functional magnetic resonance imaging during performance of an A-X version of the Continuous Performance Test. RESULTS: Patients with schizophrenia demonstrated deficits in dorsolateral PFC activation in task conditions requiring context processing but showed intact activation of posterior and inferior PFC. In addition, patients demonstrated intact activation of the primary motor and somatosensory cortex in response to stimulus processing demands. CONCLUSIONS: These results demonstrate selectivity in dorsolateral PFC dysfunction among medication-naive first-episode patients with schizophrenia, suggesting that a specific deficit in PFC function is present at illness onset, prior to the administration of medication or the most confounding effects of illness duration. Furthermore, these results are consistent with the hypothesis that WM deficits in patients with schizophrenia reflect an impairment in context processing due to a disturbance in dorsolateral PFC function.

The anatomy of auditory word processing: individual variability.

This study used functional magnetic resonance imaging (fMRI) to investigate the neural substrate underlying the processing of single words, comparing activation patterns across subjects and within individuals. In a word repetition task, subjects repeated single words aloud with instructions not to move their jaws. In a control condition involving reverse speech, subjects heard a digitally reversed speech token and said aloud the word "crime." The averaged fMRI results showed activation in the left posterior temporal and inferior frontal regions and in the supplementary motor area, similar to previous PET studies. However, the individual subject data revealed variability in the location of the temporal and frontal activation. Although these results support previous imaging studies, demonstrating an averaged localization of auditory word processing in the posterior superior temporal gyrus (STG), they are more consistent with traditional neuropsychological data, which suggest both a typical posterior STG localization and substantial individual variability. By using careful head restraint and movement analysis and correction methods, the present study further demonstrates the feasibility of using overt articulation in fMRI experiments.

Somatotopy in human primary motor and somatosensory hand representations revisited.

High-resolution functional magnetic resonance imaging of healthy volunteers was used to study the functional anatomy of the human primary motor (M1) and somatosensory (S1) cortical hand representations during simple movements of thumb, little finger and wrist and a sequential movement of the middle three fingers. Rest served as a control state. The results demonstrated an orderly somatotopy in both M1 and S1, even though the cortical areas active with individual movements significantly overlapped. Moreover, the activation patterns in M1 and S1 differed in three aspects: (i) S1 activation was distributed into significantly more clusters than M1 and the primary cluster was smaller; (ii) the overlaps of areas active with different movements were significantly larger in M1 than in S1; (iii) the difference between the three-finger sequential movement and the single-finger movements was more pronounced in S1 than in M1. The sequence-activated S1 cortex was distributed into significantly more clusters. There was also a trend for a bigger volume difference between sequence and the single finger movements in S1 than M1. These data suggest that while the distributed character dominates in M1 and S1, a somatotopic arrangement exists for both M1 and S1 hand representations, with the S1 somatotopy being more discrete and segregated, in contrast to the more integrated and overlapping somatotopy in M1.

Tracking the hemodynamic responses to reward and punishment in the striatum.

Research suggests that the basal ganglia complex is a major component of the neural circuitry that mediates reward-related processing. However, human studies have not yet characterized the response of the basal ganglia to an isolated reward, as has been done in animals. We developed an event-related functional magnetic resonance imaging paradigm to identify brain areas that are activated after presentation of a reward. Subjects guessed whether the value of a card was higher or lower than the number 5, with monetary rewards as an incentive for correct guesses. They received reward, punishment, or neutral feedback on different trials. Regions in the dorsal and ventral striatum were activated by the paradigm, showing differential responses to reward and punishment. Activation was sustained following a reward feedback, but decreased below baseline following a punishment feedback.

Three-dimensional tailored RF pulses for the reduction of susceptibility artifacts in T(*)(2)-weighted functional MRI.

A three-dimensional tailored RF pulse method for reducing intravoxel dephasing artifacts in T *(2)-weighted functional MRI is presented. A stack of spirals k-space trajectory is employed to excite a disk of magnetization for small tip angles. Smaller disks with a linear through-plane phase are inserted into the disk to locally refocus regions which are normally dephased due to susceptibility variations. Numerical simulations and imaging experiments which use the tailored RF pulses are presented. Limitations of the method and improvements are also discussed.

Working memory for letters, shapes, and locations: fMRI evidence against stimulus-based regional organization in human prefrontal cortex.

Investigations of working memory (WM) systems in the frontal cortex have revealed two stimulus dimensions along which frontal cortical representations may be functionally organized. One hypothesized dimension dissociates verbal from nonverbal WM processes, dividing left from right frontal regions. The second hypothesized dimension dissociates spatial from nonspatial WM, dividing dorsal from ventral frontal regions. Here we used functional magnetic resonance imaging to probe WM processes associated with three different types of stimuli: letters (verbal and nonspatial), abstract shapes (nonverbal and nonspatial), and locations (nonverbal and spatial). In a series of three experiments using the "n-back" WM paradigm, direct statistical comparisons were made between activation patterns in each pairwise combination of the three stimulus types. Across the experiments, no regions that demonstrated responses to WM manipulations were discovered to be unique to any of the three stimulus types. Therefore, no evidence was found to support either a left/right verbal/nonverbal dissociation or a dorsal/ventral spatial/nonspatial dissociation. While this could reflect a limitation of the present behavioral and imaging techniques, other factors that could account for the data are considered, including subjects' strategy selection, encoding of information into WM, and the nature of representational schemes in prefrontal cortex.

Anterior cingulate and the monitoriing of response conflict: evidence from an fMRI study of overt verb generation.

Studies of a range of higher cognitive functions consistently activate a region of anterior cingulate cortex (ACC), typically posterior to the genu and superior to the corpus collosum. In particular, this ACC region appears to be active in task situations where there is a need to override a prepotent response tendency, when responding is underdetermined, and when errors are made. We have hypothesized that the function of this ACC region is to monitor for the presence of "crosstalk" or competition between incompatible responses. In prior work, we provided initial support for this hypothesis, demonstrating ACC activity in the same region both during error trials and during correct trials in task conditions designed to elicit greater response competition. In the present study, we extend our testing of this hypothesis to task situations involving underdetermined responding. Specifically, 14 healthy control subjects performed a verb-generation task during event-related functional magnetic resonance imaging (fMRI), with the on-line acquisition of overt verbal responses. The results demonstrated that the ACC, and only the ACC, was more active in a series of task conditions that elicited competition among alternative responses. These conditions included a greater ACC response to: (1) Nouns categorized as low vs. high constraint (i.e., during a norming study, multiple verbs were produced with equal frequency vs. a single verb that produced much more frequently than any other); (2) the production of verbs that were weak associates, rather than, strong associates of particular nouns; and (3) the production of verbs that were weak associates for nouns categorized as high constraint. We discuss the implication of these results for understanding the role that the ACC plays in human cognition.