Interhemispheric transfer of visual information: Meaningfulness and response formation.

We examined whether Redundancy Gain (RG) can be dissociated from the response stage of a go/nogo paradigm, and whether the meaningfulness of a stimulus modulates the stage at which interhemispheric transfer occurs. Experiment 1 used a lateralized match-to-category paradigm, taken from categories with varying meaningfulness. Experiment 2 presented a novel design, which separates the perceptual stage from response formation, in examination of RG. A sequence of two stimuli was presented. Participants responded by matching the category of the second stimulus to that of the first. The redundant stimulus could appear at the first or the second stage, thus redundancy gain could be separated from the response. Experiment 1 revealed that redundancy gain occurs earlier in the process of stimulus identification for highly meaningful stimuli than for less meaningful stimuli. The results of Experiment 2 support the hypothesis that redundancy gain results from interhemispheric integration of perceptual information, rather than response-formation. Results from both experiments suggest that redundancy gain arises from interhemispheric integration in the perceptual stage, and the efficiency of this integration depends on the meaningfulness of the stimulus. These results are relevant to current hypotheses about the physiological mechanisms underlying RG.

Learning from the other limb's experience: sharing the 'trained' M1 representation of the motor sequence knowledge.

KEY POINTS: Participants were scanned during the untrained-hand performance of a motor sequence, intensively trained a day earlier, and also a similarly constructed but novel, untrained sequence. The superior performance levels for the trained, compared to the untrained sequence, were associated with a greater magnitude of activity within the primary motor cortex (M1), bilaterally, for the trained sequence. The differential responses in the 'trained' M1, ipsilateral to the untrained hand, were positively correlated with experience-related differences in the functional connectivity between the 'trained' M1 and (1) its homologue and (2) the dorsal premotor cortex (PMd) within the contralateral hemisphere. No significant correlation was evident between experience-related differences in M1 - M1 and M1 - PMd connectivity measures. These results suggest that the transfer of sequence-specific information between the two primary motor cortices is predominantly mediated by excitatory mechanisms driven by the 'trained' M1 via two independent neural pathways. Following unimanual training on a novel sequence of movements, sequence-specific performance may improve overnight not only in the trained hand, but also in the hand afforded no actual physical experience. It is not clear, however, how transfer to the untrained hand is achieved. In the present study, we examined whether and how interaction between the two primary motor cortices contributes to the performance of a sequence of movements, extensively trained the day before, by the untrained hand. Accordingly, we studied participants during the untrained-hand performance of a finger-to-thumb opposition sequence (FOS), intensively trained a day earlier (T-FOS), and a similarly constructed, but novel, untrained FOS (U-FOS). Changes in neural signals driven by task performance were assessed using functional magnetic resonance imaging. To minimize potential differences as a result of the rate of sequence execution per se, participants performed both sequences at an identical paced rate. The analyses showed that the superior fluency in executing the T-FOS compared to the U-FOS was associated with higher activity within the primary motor cortex (M1), bilaterally, for the T-FOS. The differential responses in the 'trained' M1 were positively correlated with experience-related differences in the functional connectivity between the 'trained' M1 and (1) its left homologue and (2) the left dorsal premotor cortex. However, no significant correlation was evident between the changes in connectivity in these two routes. These results suggest that the transfer of sequence-specific information between the two primary motor cortices is predominantly mediated by excitatory mechanisms driven by the 'trained' M1 via at least two independent neural pathways.

Patterns of modulation in the activity and connectivity of motor cortex during the repeated generation of movement sequences.

It is not clear how the engagement of motor mnemonic processes is expressed in online brain activity. We scanned participants, using fMRI, during the paced performance of a finger-to-thumb opposition sequence (FOS), intensively trained a day earlier (T-FOS), and a similarly constructed, but novel, untrained FOS (U-FOS). Both movement sequences were performed in pairs of blocks separated by a brief rest interval (30 sec). We have recently shown that in the primary motor cortex (M1) motor memory was not expressed in the average signal intensity but rather in the across-block signal modulations, that is, when comparing the first to the second performance block across the brief rest interval. Here, using an M1 seed, we show that for the T-FOS, the M1-striatum functional connectivity decreased across blocks; however, for the U-FOS, connectivity within the M1 and between M1 and striatum increased. In addition, in M1, the pattern of within-block signal change, but not signal variability per se, reliably differentiated the two sequences. Only for the U-FOS and only within the first blocks in each pair, the signal significantly decreased. No such modulation was found within the second corresponding blocks following the brief rest interval in either FOS. We propose that a network including M1 and striatum underlies online motor working memory. This network may promote a transient integrated representation of a new movement sequence and readily retrieves a previously established movement sequence representation. Averaging over single events or blocks may not capture the dynamics of motor representations that occur over multiple timescales.

Done that: short-term repetition related modulations of motor cortex activity as a stable signature for overnight motor memory consolidation.

An almost universally accepted tacit expectation is that learning and memory consolidation processes must be reflected in the average brain activity in brain areas relevant to task performance. Motor cortex (M1) plasticity has been implicated in motor skill acquisition and its consolidation. Nevertheless, no consistent pattern of changes in the average signal, related to motor learning or motor memory consolidation following a single session of training, has emerged from imaging studies. Here we show that the pattern and magnitude of short-term brain activity modulations in response to task repetition, in M1, may provide a robust signature for effective motor memory consolidation processes. We studied participants during the paced performance of a finger-to-thumb opposition sequence (FOS), intensively trained a day earlier, and a similarly constructed untrained FOS. In addition to within-session "on-line" gains, most participants expressed delayed, consolidation-phase gains in the performance of the trained FOS. The execution of the trained FOS induced repetition enhancements in the contralateral M1 and bilaterally in the medial-temporal lobes, offsetting novelty-related repetition suppression effects. Moreover, the M1 modulations were positively correlated with the magnitude of each participant's overnight delayed gains but not with absolute performance levels. Our results suggest that short-term enhancements of brain signals upon task repetition reflect the effectiveness of overnight motor memory consolidation. We propose that procedural memory consolidation processes may affect the excitation-inhibition balance within cortical representations of the trained movements; this new balance is better reflected in repetition effects than in the average level of evoked neural activity.

Impaired associative taste learning and abnormal brain activation in kinase-defective eEF2K mice.

Memory consolidation is defined temporally based on pharmacological interventions such as inhibitors of mRNA translation (molecular consolidation) or post-acquisition deactivation of specific brain regions (systems level consolidation). However, the relationship between molecular and systems consolidation are poorly understood. Molecular consolidation mechanisms involved in translation initiation and elongation have previously been studied in the cortex using taste-learning paradigms. For example, the levels of phosphorylation of eukaryotic elongation factor 2 (eEF2) were found to be correlated with taste learning in the gustatory cortex (GC), minutes following learning. In order to isolate the role of the eEF2 phosphorylation state at Thr-56 in both molecular and system consolidation, we analyzed cortical-dependent taste learning in eEF2K (the only known kinase for eEF2) ki mice, which exhibit reduced levels of eEF2 phosphorylation but normal levels of eEF2 and eEF2K. These mice exhibit clear attenuation of cortical-dependent associative, but not of incidental, taste learning. In order to gain a better understanding of the underlying mechanisms, we compared brain activity as measured by MEMRI (manganese-enhanced magnetic resonance imaging) between eEF2K ki mice and WT mice during conditioned taste aversion (CTA) learning and observed clear differences between the two but saw no differences under basal conditions. Our results demonstrate that adequate levels of phosphorylation of eEF2 are essential for cortical-dependent associative learning and suggest that malfunction of memory processing at the systems level underlies this associative memory impairment.

Changes in Brain Volume Resulting from Cognitive Intervention by Means of the Feuerstein Instrumental Enrichment Program in Older Adults with Mild Cognitive Impairment (MCI): A Pilot Study.

There is increasing interest in identifying biological and imaging markers for the early detection of neurocognitive decline. In addition, non-pharmacological strategies, including physical exercise and cognitive interventions, may be beneficial for those developing cognitive impairment. The Feuerstein Instrumental Enrichment (FIE) Program is a cognitive intervention based on structural cognitive modifiability and the mediated learning experience (MLE) and aims to promote problem-solving strategies and metacognitive abilities. The FIE program uses a variety of instruments to enhance the cognitive capacity of the individual as a result of mediation. A specific version of the FIE program was developed for the cognitive enhancement of older adults, focusing on strengthening orientation skills, categorization skills, deductive reasoning, and memory. We performed a prospective interventional pilot observational study on older subjects with MCI who participated in 30 mediated FIE sessions (two sessions weekly for 15 weeks). Of the 23 subjects who completed the study, there was a significant improvement in memory on the NeuroTrax cognitive assessment battery. Complete sets of anatomical MRI data for voxel-based morphometry, taken at the beginning and the end of the study, were obtained from 16 participants (mean age 83.5 years). Voxel-based morphometry showed an interesting and unexpected increase in grey matter (GM) in the anterolateral occipital border and the middle cingulate cortex. These initial findings of our pilot study support the design of randomized trials to evaluate the effect of cognitive training using the FIE program on brain volumes and cognitive function.

The Endogenous Analgesia Signature in the Resting Brain of Healthy Adults and Migraineurs.

Altered pain modulation and resting state functional connectivity (rsFC) were found to be related to migraine pathology and clinical manifestation. We examined how pain modulation psychophysical measures are related to resting-state networks and rsFC between bottom-up and top-down pain modulation areas. Thirty-two episodic migraineurs and 23 age-matched healthy individuals underwent temporal summation of pain (TSOP) and conditioned pain modulation (CPM) tests, followed by a resting-state imaging scan. No differences in temporal summation of pain and CPM were found between groups. However, in healthy individuals, more efficient CPM was correlated with 1) stronger rsFCs of the posterior cingulate cortex, with the ventromedial prefrontal cortex and with the pregenual anterior cingulate cortex; 2) weaker rsFC of the anterior insula with the angular gyrus. Conversely, in migraineurs, the association between CPM and rsFC was altered. Our results suggest that the functional connectivity within the default mode network (DMN) components and the functional coupling between the DMN and pain inhibitory brain areas is linked with pain inhibition efficiency. In migraineurs, this interplay is changed, yet enables normal pain inhibition. Our findings shed light on potential functional adaptation of the DMN and its role in pain inhibition in health and migraine. PERSPECTIVE: This article establishes evidence for the relationship between the resting-state brain and individual responses in psychophysical pain modulation tests, in both migraine and healthy individuals. The results emphasize the significant role of the default mode network in maintaining pain inhibition efficiency in health and in the presence of chronic pain.

A new method to record and control for 2D-movement kinematics during functional magnetic resonance imaging (fMRI).

The recording of movement kinematics during functional magnetic resonance imaging (fMRI) experiments is complicated due to technical constraints of the imaging environment. Nevertheless, to study the functions of brain areas related to motor control, reliable and accurate records of movement trajectories and speed profiles are needed. We present a method designed to record and characterize the kinematic properties of drawing- and handwriting-like forearm movements during fMRI studies by recording pen stroke trajectories. The recording system consists of a translucent plastic board, a plastic pen containing fiber optics and a halogen light power source, a CCD camera, a video monitor and a PC with a video grabber card. Control experiments using a commercially available digitizer tablet have demonstrated the reliability of the data recorded during fMRI. Since the movement tracking signal is purely optical, there is no interaction with the MR (echoplanar) images. Thus, the method allows to obtain movement records with high spatial and temporal resolution which are suitable for the kinematic analysis of hand movements in fMRI studies.

In vivo occipital-frontal temperature-gradient in schizophrenia patients and its possible association with psychopathology: a magnetic resonance spectroscopy study.

BACKGROUND: Accumulating data suggest that schizophrenia patients' mental status might be modulated by their core/brain temperature. Hence, we intended to assess in vivo brain temperature (Tb) of schizophrenia patients vs. healthy subjects and to evaluate its potential association with patients' mental status. METHODS: Absolute values of Tb were measured in 9 neuroleptic-treated schizophrenia patients and 10 healthy comparison subjects using 1H magnetic resonance spectroscopy (MRS). Values were extracted by measuring the chemical shift between the peaks of water and N-acetyl-aspartate in the 1H MRS spectra. RESULTS: A substantial (about 1.1 degrees C) and significantly higher occipital-frontal temperature-gradient was found in the schizophrenia patients compared to the healthy controls (1.27 degrees C vs. 0.18 degrees C; p=0.032). Furthermore, a trend was found between the above mentioned occipital-frontal temperature-gradient in the schizophrenia patients and the severity of their psychopathology, as assessed by the total Positive and Negative Syndrome Scale (PANSS) scores (r=0.61; p=0.08). CONCLUSIONS: Our findings corroborate previous results indicating putative correlation between core/brain temperature and the mental status of schizophrenia patients, emphasizing the possible role of within patients decreased frontal temperature and a significant occipital-frontal temperature-gradient as modulators of psychopathology. In addition, the MRS technique used for brain temperature assessment seems to be a potential non-invasive method to assess in vivo absolute Tb in schizophrenia.

Do patients with interictal migraine modulate pain differently from healthy controls? A psychophysical and brain imaging study.

Studies in interictal migraine show either normal or impaired pain modulation, at the psychophysical level. To date, pain modulation in migraineurs has yet to be explored concurrent with imaging methods. We aimed to investigate brain activity associated with endogenous analgesia by functional magnetic resonance imaging in attack-free migraineurs. Thirty-nine episodic migraineurs and 35 controls participated. Endogenous analgesia efficiency was assessed by the conditioned pain modulation (CPM) paradigm during functional magnetic resonance imaging. Conditioned pain modulation included 4 stimulation sequences of either test stimulus (noxious contact heat at forearm) given stand alone (Ts_alone) or concomitant to contralateral foot immersion in cold water (Ts_conditioned). The psychophysical CPM (Ts_conditioned minus Ts_alone; 0-10 numerical rating scale) and related brain activity were examined. No group differences were found in the psychophysical CPM (controls: -0.52 ± 0.80; migraineurs: -0.20 ± 0.88; repeated-measures analysis of variance: P = 0.110) or related brain activity (family wise error [P < 0.05] correction at the voxel level). Within groups, controls showed a significant CPM effect (Ts_alone: 6.15 ± 2.03 vs Ts_conditioned: 5.63 ± 1.97; P < 0.001), whereas migraineurs did not (Ts_alone: 5.60 ± 1.92 vs Ts_conditioned: 5.39 ± 2.30; P = 0.153); yet, both groups showed significant CPM-related decreased deactivation in prefrontal areas including the superior frontal gyrus and parietal regions including precuneus. The change in brain activity seems related to task demands rather than to pain reduction. The lack of group difference between migraineurs and controls in CPM and its related brain activity may result from (1) the specific CPM methodology used in this study, since migraineurs are reported to show various pain modulation efficiency for different test paradigms and/or (2) pathophysiological diversity of patients with migraine.

Effects of alphabeticality, practice and type of instruction on reading an artificial script: an fMRI study.

In neuroimaging studies of word reading in natural scripts, the effect of alphabeticality is often confounded with the effect of practice. We used an artificial script to separately manipulate the effects of practice and alphabeticality following training with and without explicit letter instructions. Participants received multi-session training in reading nonsense words, written in an artificial script, wherein each phoneme was represented by 2 discrete symbols . Three training conditions were compared: alphabetical whole words with letter decoding instruction (explicit); alphabetical whole-words (implicit) and non-alphabetical whole-words (arbitrary). Each participant was trained on the arbitrary condition and on one of the alphabetical conditions (explicit or implicit). fMRI scans were acquired after training during reading of trained words and relatively novel words in the alphabetical and arbitrary conditions. Our results showed greater activation in the explicit compared to the arbitrary conditions, but only for relatively-novel words, in the left posterior inferior frontal gyrus (IFG). In the implicit condition, the left posterior IFG was active in both trained and relatively novel words. These results indicate the involvement of the left posterior IFG in letter decoding, and suggest that reading of explicitly well-trained words did not rely on letter decoding, while in implicitly trained words letter decoding persisted into later stages. The superior parietal lobules showed reduced activation for items that received more practice, across all training conditions. Altogether, our results suggest that the alphabeticality of the word, the amount of practice and type of instructions have independent and interacting effects on brain activation during reading.

A word by any other intonation: fMRI evidence for implicit memory traces for pitch contours of spoken words in adult brains.

OBJECTIVES: Intonation may serve as a cue for facilitated recognition and processing of spoken words and it has been suggested that the pitch contour of spoken words is implicitly remembered. Thus, using the repetition suppression (RS) effect of BOLD-fMRI signals, we tested whether the same spoken words are differentially processed in language and auditory brain areas depending on whether or not they retain an arbitrary intonation pattern. EXPERIMENTAL DESIGN: Words were presented repeatedly in three blocks for passive and active listening tasks. There were three prosodic conditions in each of which a different set of words was used and specific task-irrelevant intonation changes were applied: (i) All words presented in a set flat monotonous pitch contour (ii) Each word had an arbitrary pitch contour that was set throughout the three repetitions. (iii) Each word had a different arbitrary pitch contour in each of its repetition. PRINCIPAL FINDINGS: The repeated presentations of words with a set pitch contour, resulted in robust behavioral priming effects as well as in significant RS of the BOLD signals in primary auditory cortex (BA 41), temporal areas (BA 21 22) bilaterally and in Broca's area. However, changing the intonation of the same words on each successive repetition resulted in reduced behavioral priming and the abolition of RS effects. CONCLUSIONS: Intonation patterns are retained in memory even when the intonation is task-irrelevant. Implicit memory traces for the pitch contour of spoken words were reflected in facilitated neuronal processing in auditory and language associated areas. Thus, the results lend support for the notion that prosody and specifically pitch contour is strongly associated with the memory representation of spoken words.

Time-Resolved and Spatio-Temporal Analysis of Complex Cognitive Processes and their Role in Disorders like Developmental Dyscalculia.

The aim of this article is to report on the importance and challenges of a time-resolved and spatio-temporal analysis of fMRI data from complex cognitive processes and associated disorders using a study on developmental dyscalculia (DD). Participants underwent fMRI while judging the incorrectness of multiplication results, and the data were analyzed using a sequence of methods, each of which progressively provided more a detailed picture of the spatio-temporal aspect of this disease. Healthy subjects and subjects with DD performed alike behaviorally though they exhibited parietal disparities using traditional voxel-based group analyses. Further and more detailed differences, however, surfaced with a time-resolved examination of the neural responses during the experiment. While performing inter-group comparisons, a third group of subjects with dyslexia (DL) but with no arithmetic difficulties was included to test the specificity of the analysis and strengthen the statistical base with overall fifty-eight subjects. Surprisingly, the analysis showed a functional dissimilarity during an initial reading phase for the group of dyslexic but otherwise normal subjects, with respect to controls, even though only numerical digits and no alphabetic characters were presented. Thus our results suggest that time-resolved multi-variate analysis of complex experimental paradigms has the ability to yield powerful new clinical insights about abnormal brain function. Similarly, a detailed compilation of aberrations in the functional cascade may have much greater potential to delineate the core processing problems in mental disorders.

Alternation learning in pathological gamblers: an fMRI Study.

OBJECTIVES: We have previously reported that pathological gamblers have impaired performance on the Stroop color word naming task, go-no-go task and speed accuracy tradeoff performance, tasks used to assess executive function and interference control. The aim of the present neuroimaging study was to explore the relationship between frontal cortex function and gambling severity in pathological gamblers. MATERIALS AND METHODS: Functional MRI (fMRI) was used to estimate brain activity of ten male medication-free pathological gamblers during performance of an alternation learning task. Performance of this task has been shown to depend on the function of regions in the frontal cortex. RESULTS: The executive functions needed to perform the alternation learning task were expressed as brain activation in lateral and medial frontal as well as parietal and occipital regions. By correlating the level of local brain activation to task performance, parietal regions and lateral frontal and orbitofrontal regions were demonstrated. A higher score in SOGS was associated with intrusion on the task-specific activation in the left hemisphere, to some extant in parietal regions and even more pronouncedly in left frontal and orbitofrontal regions. CONCLUSIONS: Our preliminary data suggests that pathological gambling may be characterized by specific neuro-cognitive changes related to the frontal cortex.

Alteration learning in social anxiety disorder: an fMRI study.

The present study attempts to challenge the orbitofrontal cortex by using a learning paradigm which is specifically subserved by this cortical region. We implemented a version of alternation learning specifically designed for fMRI and assessed the cognitive performance and fMRI response in wide range of social anxiety disorder (SAD) severity (n=15). The main regions that were activated by the alternation learning task included portions of frontal and orbitofrontal cortex as well as the calcarine fissure. Correlations between brain activation and performance of the alternation learning task were found, among other regions, in the left and right orbitofrontal cortex. Highest correlations between degree of activation and the anxiety scores as assessed by the Leibovitch Social Anxiety Scale (LSAS) were obtained in the left temporal region as well as orbitofrontal cortex. This study supports the involvement of the orbitofrontal cortex in emotion and cognitive regulation in SAD.

Abnormal olfactory function demonstrated by manganese-enhanced MRI in mice with experimental neuropsychiatric lupus.

Mice with experimental neuropsychiatric lupus (NPSLE), induced by anti-ribosomal-P antibodies, developed depression-like behavior and a diminished sense of smell. Manganese-enhanced MRI (MEMRI) allows in vivo mapping of functional neuronal connections in the brain, including the olfactory tract. The aim of this study was to analyze and describe, via the MEMRI technique, the effect of the anti-ribosomal-P injection on the olfactory pathway. Twenty mice were intra-cerebra-ventricular injected to the right hemisphere: 10 with human anti-ribosomal-P antibodies and 10 with human IgG antibodies (control). Depression was addressed by forced swimming test and smell function was evaluated by smelling different concentrations of menthol. MEMRI was used to investigate the olfactory system in these mice. Passive transfer of anti-ribosomal-P to mice resulted in a depression-like behavior, accompanied with a significant deficit in olfactory function. MEMRI of these mice demonstrated significant reduction (P < 0.001) in normalized manganese enhancement ratios of olfactory structures, compared to control mice. We concluded that an impaired olfactory neuronal function in mice with experimental depression, mediated by passive transfer of human-anti-ribosomal-P, can be demonstrated by MEMRI.