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Introduction The observed variability in the effects of transcranial direct current stimulation (tDCS) is influenced by the amount of current reaching the targeted region-of-interest (ROI). Age and sex might affect current density at target ROI due to their impact on cortical anatomy. The present tDCS simulation study investigates the effects of cortical anatomical parameters (volumes, dimension, and torque) on simulated tDCS current density in healthy young, middle-aged, and older males and females. Methodology Individualized head models from 240 subjects (120 males, 18–87 years of age) were used to identify the estimated current density (2 mA current intensity, 25 cm2 electrode) from two simulated tDCS montages (CP5_CZ and F3_FP2) targeting the inferior parietal lobule (IPL) and middle frontal gyrus (MFG), respectively. Cortical parameters including segmented brain volumes (cerebrospinal fluid [CSF], grey and white matter), cerebral-dimensions ( length / width & length / height ) and brain-torque (front and back shift, petalia, and bending) were measured using the magnetic resonance images (MRIs) from each subject. The present study estimated sex differences in current density at these target ROIs mediated by these cortical parameters within each age group. Results For both tDCS montages, females in the older age group received higher current density than their male counterparts at the target ROIs. No sex differences were observed in the middle-aged group. Males in the younger age group had a higher current density than females, only for the parietal montage. Across all age groups, CSF, and grey matter volumes significantly predicted the current intensity estimated at the target sites. In the older age group only, brain-torque was a significant mediator of the sex difference. Conclusions Our findings demonstrate the presence of sex differences in the simulated tDCS current density, however this pattern differed across age groups and stimulation locations. Future studies should consider influence of age and sex on individual cortical anatomy and tailor tDCS stimulation parameters accordingly.

Several fMRI studies have shown that the superior cerebellum exhibits load-dependent activations during encoding of letters in a Sternberg verbal working memory (VWM) task. It has been hypothesized that the cerebellum regulates the acquisition of sensory data across all modalities, and thus, that VWM load activations may reflect high- vs low-load differences in sensory acquisition demands. Therefore, increased difficulty in sensory data acquisition should elicit greater activation in the cerebellum. The present fMRI study manipulated sensory acquisition in VWM by presenting visually degraded and non-degraded stimuli with high and low memory loads, thereby identifying load-dependent regions of interest in the cerebellum, and then testing if these regions showed greater activation for degraded stimuli. Results yielded partial support for the sensory acquisition hypothesis in a load-dependent region of the vermis, which showed significantly greater activation for degraded relative to non-degraded stimuli. Because eye movements did not differ for these stimulus types, and degradation-related activations were present after co-varying eye movements, this activation appears to be related to perceptual rather than oculomotor demands. In contrast to the vermis, load-sensitive regions of the cerebellar hemispheres did not show increased activation for degraded stimuli. These findings point to an overall function of association-based prediction that may underlie general cerebellar function, with perceptual prediction of stimuli from partial representations occurring in the vermis, and articulatory prediction occurring in the hemispheres.

Contingency awareness is thought to rely on an intact medial temporal lobe and also appears to be a function of age, as older subjects tend to be less aware. The current investigation used functional magnetic resonance imaging, transcranial direct current stimulation, and eyeblink classical conditioning to study brain processes related to contingency awareness as a function of age. Older adults were significantly less aware of the relationship between the tone-airpuff pairings than younger adults. Greater right parietal functional magnetic resonance imaging activation was associated with higher levels of contingency awareness for younger and older subjects. Cathodal transcranial direct current stimulation over the right parietal lobe led to lower levels of awareness in younger subjects without disrupting conditioned responses. Older adults exhibited hyperactivations in the parietal and medial temporal lobes, despite showing no conditioning deficits. These findings strongly support the idea that the parietal cortex serves as a substrate for contingency awareness and that age-related disruption of this region is sufficient to impair awareness, which may be a manifestation of some form of naturally occurring age-related neglect.

The phonological loop is part of the Baddeley’s verbal working memory (VWM) model that stores phonological information and refreshes its contents through an articulatory process. Many studies have reported the cerebellum’s involvement during VWM tasks. In the motor literature, the cerebellum is thought to support smooth and rapid movement sequences through internal models that simulate the action of motor commands, then use the error signals generating from the discrepancy between the predicted and actual sensory consequences to adjust the motor system. Here, we hypothesize that a similar monitoring and error-driven adjustment process can be extended to VWM; specifically, the cerebellum checks for discrepancies between the predicted and actual articulatory process to ensure the accuracy and fluency of articulatory rehearsal. During neuroimaging, participants rehearsed a sequence of letters in sync with the presentation of a visual pacing stimulus (#) that was terminated by the occurrence of a probe letter. Participants judged whether the probe was the correct letter in the sequence (i.e., match trial), or deviated from the sequence (i.e., mismatch trial). Detection of sequence violation was not only associated with prolonged reaction time but also an increased activation in a left executive control network. Psychophysiological interaction was used to investigate whether the cerebellum interacts with the cerebral cortex for error monitoring and adjustments. We found increased functional connectivity between the right cerebellum and the cerebral cortex during mismatch relative to match probes, indicating sequence violation resulting in greater cerebellar connectivity with areas in the cerebral cortex involved in phonological sequencing.

BackgroundTranscranial Direct Current Stimulation (tDCS) is a technique where a weak current is passed through the electrodes placed on the scalp. The distribution of the electric current induced in the brain due to tDCS is provided by simulation toolbox like Realistic-volumetric-Approach-based-Simulator-for-Transcranial-electric-stimulation (ROAST). However, the procedure to estimate the total current density induced at the target and the intermediary region of the cortex is complex. The Systematic-Approach-for-tDCS-Analysis (SATA) was developed to overcome this problem. However, SATA is limited to standardized headspace only. Here we develop individual-SATA (𝓲-SATA) to extend it to individual head.MethodT1-weighted images of 15 subjects were taken from two Magnetic Resonance Imaging (MRI) scanners of different strengths. Across the subjects, the montages were simulated in ROAST. 𝓲-SATA converts the ROAST output to Talairach space. The x, y and z coordinates of the anterior commissure (AC), posterior commissure (PC), and Mid-Sagittal (MS) points are necessary for the conversion. AC and PC are detected using the acpcdetect toolbox. We developed a method to determine the MS in the image and cross-verified its location manually using BrainSight®.ResultDetermination of points with 𝓲-SATA is fast and accurate. The 𝓲-SATA provided estimates of the current-density induced across an individual’s cortical lobes and gyri as tested on images from two different scanners.ConclusionResearchers can use 𝓲-SATA for customizing tDCS-montages. With 𝓲-SATA it is also easier to compute the inter-individual variation in current-density across the target and intermediary regions of the brain. The software is publicly available.

BACKGROUND: Functional MRI (fMRI) task-related analyses rely on an estimate of the brain’s hemodynamic response function (HRF) to model the brain’s response to events. Although changes in the HRF have been found after acute alcohol administration, the effects of heavy chronic alcohol consumption on the HRF have not been explored, and the potential benefits or pitfalls of estimating each individual’s HRF on fMRI analyses of chronic alcohol use disorder are not known. METHODS: Participants with alcohol use disorder (AUD) and controls (CTL) received structural, functional, and vascular scans. During fMRI, participants were cued to tap their fingers, and averaged responses were extracted from the motor cortex. Curve fitting on these HRFs modeled them as a difference between 2 gamma distributions, and the temporal occurrence of the main peak and undershoot of the HRF was computed from the mean of the first and second gamma distributions, respectively. RESULTS: ANOVA and regression analyses found that the timing of the HRF undershoot, increased significantly as a function of total lifetime drinking. Although gray matter volume in the motor cortex decreased with lifetime drinking, this was not sufficient to explain the undershoot timing shifts, and vascular factors measured in the motor cortex did not differ among groups. Comparison of random effects analyses using custom fitted and canonical HRFs for CTL and AUD groups showed better results throughout the brain for custom fitted versus canonical HRF for CTL subjects. For AUD subjects, the same was true except for the basal ganglia. CONCLUSIONS: These findings suggest that excessive alcohol consumption is associated with changes in the HRF undershoot. HRF changes could provide a possible biomarker for the effects of lifetime drinking on brain function. Changes in HRF topography affect fMRI activation measures, and subject-specific HRFs generally improve fMRI activation results.

Verbal working memory is one of the most studied non-motor functions with robust cerebellar involvement. While the superior cerebellum (lobule VI) has been associated with articulatory control, the inferior cerebellum (lobule VIIIa) has been linked to phonological storage. The present study was aimed to elucidate the differential roles of these regions by investigating whether the cerebellum might contribute to verbal working memory via predictions based on sequence learning/detection. 19 healthy adult subjects completed an fMRI-based Sternberg task which included repeating and novel letter sequences that were phonologically similar or dissimilar. It was hypothesized that learning a repeating sequence of study letters would reduce phonological storage demand and associated right inferior cerebellar activations and that this effect would be modulated by phonological similarity of the study letters. Specifically, while increased phonological storage demand due to high phonological similarity was expected to be reflected in increased right inferior cerebellar activations for similar relative to dissimilar study letters, the reduction in activation for repeating relative to novel sequences was expected to be more profound for phonologically similar than for dissimilar study letters, especially at higher memory load. Results confirmed the typical effects of cognitive load (5 vs. 2 study letters) and phonological similarity in several cerebellar and neocortical brain regions as well as in behavioral data (accuracy and response time). Importantly, activations in superior and inferior cerebellar regions were differentially modulated as a function of similarity and sequence novelty, indicating that particularly lobule VIIIa may contribute to verbal working memory by generating predictions of letter sequences that reduce the likelihood of phonological loop failure before stored items need to be retrieved. The present study is consistent with other investigations that support prediction, which can be based on sequence learning or detection, as an overarching cerebellar function. Electronic supplementary material The online version of this article (10.1007/s00429-018-1784-0) contains supplementary material, which is available to authorized users.

Transcranial direct current stimulation (tDCS) is an innovative technique recently shown to improve language outcomes even in neurodegenerative conditions such as primary progressive aphasia (PPA), but the underlying brain mechanisms are not known. The present study tested whether the additional language gains with repetitive tDCS (over sham) in PPA are caused by changes in functional connectivity between the stimulated area (the left inferior frontal gyrus (IFG)) and the rest of the language network.We scanned 24 PPA participants (11 female) before and after language intervention (written naming/spelling) with a resting-state fMRI sequence and compared changes before and after three weeks of tDCS or sham coupled with language therapy. We correlated changes in the language network as well as in the default mode network (DMN) with language therapy outcome measures (letter accuracy in written naming).Significant tDCS effects in functional connectivity were observed between the stimulated area and other language network areas and between the language network and the DMN. TDCS over the left IFG lowered the connectivity between the above pairs. Changes in functional connectivity correlated with improvement in language scores (letter accuracy as a proxy for written naming) evaluated before and after therapy.These results suggest that one mechanism for anodal tDCS over the left IFG in PPA is a decrease in functional connectivity (compared to sham) between the stimulated site and other posterior areas of the language network. These results are in line with similar decreases in connectivity observed after tDCS over the left IFG in aging and other neurodegenerative conditions. Keywords: Primary progressive aphasia (PPA), Transcranial direct current stimulation (tDCS), Resting-state fMRI (rsfMRI), Functional connectivity, Neurodegenerative diseases

BACKGROUND: Excessive alcohol consumption produces changes in the brain that often lead to cognitive impairments. One fundamental form of learning, eyeblink classical conditioning (EBC) has been widely used to study the neurobiology of learning and memory. Participants with alcohol use disorders (AUD) have consistently shown a behavioral deficit in EBC. The present functional magnetic resonance imaging (fMRI) study is the first to examine brain function during conditioning in abstinent AUD participants and healthy participants. METHODS: AUD participants met DSM-IV criteria for alcohol dependence, had at least a 10 year history of heavy drinking, and were abstinent from alcohol for at least 30 days. During fMRI, participants received auditory tones that predicted the occurrence of corneal airpuffs. Anticipatory eyeblink responses to these tones were monitored during the experiment to assess learning-related changes. RESULTS: Behavioral results indicate that AUD participants showed significant conditioning deficits and that their history of lifetime drinks corresponded to these deficits. Despite this learning impairment, AUD participants showed hyperactivation in several key cerebellar structures (including lobule VI) during conditioning. For all participants, history of lifetime drinks corresponded with their lobule VI activity. CONCLUSIONS: These findings suggest that excessive alcohol consumption is associated with abnormal cerebellar hyperactivation and conditioning impairments.

Objective. Transcranial Direct Current Stimulation (tDCS) is a technique where a weak current is passed through the electrodes placed on the scalp. The distribution of the electric current induced in the brain due to tDCS is provided by simulation toolbox like Realistic volumetric Approach based Simulator for Transcranial electric stimulation (ROAST). However, the procedure to estimate the total current density induced at the target and the intermediary region of the cortex is complex. The Systematic-Approach-for-tDCS-Analysis (SATA) was developed to overcome this problem. However, SATA is limited to standardized (MNI152) headspace only. Here we develop individual-SATA (i-SATA) to extend it to individual head. Approach. T1-weighted images of 15 subjects were taken from two Magnetic Resonance Imaging scanners of different strengths. Across the subjects, the montages were simulated in ROAST. i-SATA converts the ROAST output to Talairach space. The x, y and z coordinates of the anterior commissure (AC), posterior commissure (PC), and Mid-Sagittal (MS) points are necessary for the conversion. AC and PC are detected using the acpcdetect toolbox. We developed a method to determine the MS in the image and cross-verified its location manually using BrainSight®. Main results. Determination of points with i-SATA is fast and accurate. The i-SATA provided estimates of the current-density induced across an individual’s cortical lobes and gyri as tested on images from two different scanners. Significance. Researchers can use i-SATA for customizing tDCS-montages. With i-SATA it is also easier to compute the inter-individual variation in current-density across the target and intermediary regions of the brain. The software is publicly available.

Purpose Venous oxygenation (Yv) is an important index of brain physiology and may be indicative of brain diseases. A T2-relaxation-under-spin-tagging (TRUST) MRI technique was recently developed to measure Yv. A multisite evaluation of this technique would be an important step toward broader availability and potential clinical utilizations of Yv measures. Methods TRUST MRI was performed on a total of 250 healthy subjects, 125 from the developer's site and 25 each from five other sites. All sites were equipped with a 3 Tesla (T) MRI of the same vendor. The estimated Yv and the standard error (SE) of the estimation eYv were compared across sites. Results The averaged Yv and eYv across six sites were 61.1% ± 1.4% and 1.3% ± 0.2%, respectively. Multivariate regression analysis showed that the estimated Yv was dependent on age (P = 0.009) but not on performance site. In contrast, the SE of the Yv estimation was site-dependent (P = 0.024) but was less than 1.5%. Further analysis revealed that eYv was positively associated with the amount of subject motion (P

Background Transcranial magnetic stimulation (TMS) can be combined with functional magnetic resonance imaging (fMRI) to simultaneously manipulate and monitor human cortical responses. Although tremendous efforts have been directed at characterizing the impact of TMS on image acquisition, the influence of the scanner's static field on the TMS coil has received limited attention. Objective/hypothesis The aim of this study was to characterize the influence of the scanner's static field on TMS. We hypothesized that spatial variations in the static field could account for TMS field variations in the scanner environment. Methods Using an MRI-compatible TMS coil, we estimated TMS field strengths based on TMS-induced voltage changes measured in a search coil. We compared peak field strengths obtained with the TMS coil positioned at different locations (B 0 field vs fringe field) and orientations in the static field. We also measured the scanner's static field to derive a field map to account for TMS field variations. Results TMS field strength scaled depending on coil location and orientation with respect to the static field. Larger TMS field variations were observed in fringe field regions near the gantry as compared to regions inside the bore or further removed from the bore. The scanner's static field also exhibited the greatest spatial variations in fringe field regions near the gantry. Conclusions The scanner's static field influences TMS fields and spatial variations in the static field correlate with TMS field variations. Coil orientation changes in the B0 field did not result in substantial TMS field variations. TMS field variations can be minimized by delivering TMS in the bore or outside of the 0–70 cm region from the bore entrance.

Prenatal alcohol exposure has been linked to a broad range of developmental deficits, with eyeblink classical conditioning (EBC) among the most sensitive endpoints. This fMRI study compared EBC-related brain activity in 47 children with fetal alcohol syndrome (FAS), partial FAS (PFAS), heavily exposed (HE) non-syndromal children, and healthy controls. All of the children had previously participated in two EBC studies conducted as part of our longitudinal study of fetal alcohol spectrum disorders. Although learning-related behavioral differences were seen in all groups during the scans, controls showed more conditioned responses (CR) than the alcohol-exposed groups. Despite lower conditioning levels relative to controls, the exposed groups exhibited extensive cerebellar activations. Specifically, children with FAS/PFAS showed increased activation of cerebellar lobule VI in session 2, while HE children showed increased activation in session 1. Continuous measures of prenatal alcohol use correlated with learning-related activations in cerebellum and frontal cortices. Only controls showed significant cerebellar activation—CR correlations in the deep nuclei and lateral lobule VI, suggesting that these key regions supporting EBC may be functionally disorganized in alcohol-exposed children. These findings are the first to characterize abnormalities in brain function associated with the behavioral conditioning deficits seen in children with prenatal alcohol exposure.

Objective To demonstrate a correlation between anatomic regional changes in Spinocerebellar Ataxia type 6 (SCA6) patients and measures of cognitive performance on neuropsychological tests. Methods Neurocognitive testing was conducted on 24 SCA6 and 28 control subjects. For each cognitive test, SCA6 patients were compared against the controls using Student's t-test. For the cerebellar patients, using voxel based morphometry, correlations between cerebellar gray matter volume at each voxel and performance on the neuropsychological exams were calculated using the Pearson correlation coefficient implemented in SPM8. Results Compared to controls, SCA6 patients exhibited significantly impaired performance on the following cognitive tests: Rey-Auditory Verbal Learning Test Trial V, Controlled Oral Word Association phonemic test and semantic-verb test, Rey-Osterrieth Complex Figure copy test as well as immediate and delayed visuo-spatial memory recall test, Trail Making Test (TMT) Part A and Part B, Stroop Color Task completion time, Stroop Color-Word Task score, and Grooved Pegboard Test (GPT) Dominant and Non-Dominant Hand time. Correlations of gray matter density with cognitive test performance were determined for all SCA6 subjects. Using a p-value threshold of 0.001 and family-wise small volume error correction, significant correlations were found for GPT Non-Dominant, GPT Dominant, TMT Part A, and TMT Part B. Conclusion Different regional patterns of cerebellar involvement were found for the motoric GPT task and the executive version of the TMT. The results for the GPT strongly indicated that the integrity of medial superior hemispheric regions was associated with motor task performance, whereas executive cognitive function was localized in distinctly different inferior regions. This is the first VBM study to differentiate cognitive and motor contributions of the cerebellum.

The ability to store and manipulate online information may be enhanced by an inner speech mechanism that draws upon motor brain regions. Neural correlates of this mechanism were examined using event-related functional magnetic resonance imaging (fMRI). Sixteen participants completed two conditions of a verbal working memory task. In both conditions, participants viewed one or two target letters. In the “storage” condition, these targets were held in mind across a delay. Then a probe letter was presented, and participants indicated by button press whether the probe matched the targets. In the “manipulation” condition, participants identified new targets by thinking two alphabetical letters forward of each original target (e.g., f → h). Participants subsequently indicated whether the probe matched the newly derived targets. Brain activity during the storage and manipulation conditions was examined specifically during the delay phase in order to directly compare manipulation versus storage processes. Activations that were common to both conditions, yet disproportionately greater with manipulation, were observed in the left inferior frontal cortex, premotor cortex, and anterior insula, bilaterally in the parietal lobes and superior cerebellum, and in the right inferior cerebellum. This network shares substrates with overt speech and may represent an inner speech pathway that increases activity with greater working memory demands. Additionally, an inverse correlation was observed between manipulation-related brain activity (on correct trials) and test accuracy in the left premotor cortex, anterior insula, and bilateral superior cerebellum. This inverse relationship may represent intensification of inner speech as one struggles to maintain performance levels.

Working memory is impaired in opioid-dependent individuals, yet the neural underpinnings of working memory in this population are largely unknown. Previous studies in healthy adults have demonstrated that working memory is supported by a network of brain regions that includes a cerebro-cerebellar circuit. The cerebellum, in particular, may be important for inner speech mechanisms that assist verbal working memory. This study used functional magnetic resonance imaging (fMRI) to examine brain activity associated with working memory in 5 opioid-dependent, methadone-maintained patients and 5 matched, healthy controls. An item recognition task was administered in two conditions: 1) a low working memory load “match” condition in which participants determined whether target letters presented at the beginning of the trial matched a probe item, and 2) a high working memory load “manipulation” condition in which participants counted two alphabetical letters forward of each of the targets and determined whether either of these new items matched a probe item. Response times and accuracy scores were not significantly different between the groups. FMRI analyses indicated that, in association with higher working memory load (“manipulation” condition), the patient group exhibited hyperactivity in the superior and inferior cerebellum and amygdala relative to that of controls. At a more liberal statistical threshold, patients exhibited hypoactivity in the left prefrontal and medial frontal/pre-SMA regions. These results indicate that verbal working memory in opioid-dependent individuals involves a disrupted cerebro-cerebellar circuit, and shed light on the neuroanatomical basis of working memory impairments in this population.

Contributions of cerebro-cerebellar function to executive verbal working memory were examined using event-related functional magnetic resonance imaging (fMRI) while 16 subjects completed two versions of the Sternberg task. In both versions subjects were presented with two or six target letters during the encoding phase, which were held in memory during the maintenance phase. A single probe letter was presented during the retrieval phase. In the “match condition”, subjects decided whether the probe matched the target letters. In the “executive condition”, subjects created a new probe by counting two alphabetical letters forward (e.g., f → h) and decided whether the new probe matched the target letters. Neural activity during the match and executive conditions was compared during each phase of the task. There were four main findings. First, cerebro-cerebellar activity increased as a function of executive load. Second, the dorsal cerebellar dentate co-activated with the supplementary motor area (SMA) during encoding. This likely represented the formation of an articulatory (motor) trajectory. Third, the ventral cerebellar dentate co-activated with anterior prefrontal regions Brodmann Area (BA) 9/46 and the pre-SMA during retrieval. This likely represented the manipulation of information and formation of a response. A functional dissociation between the dorsal “motor” dentate and “cognitive” ventral dentate agrees with neuroanatomical tract tracing studies that have demonstrated separate neural pathways involving each region of the dentate: the dorsal dentate projects to frontal motor areas (including the SMA), and the ventral dentate projects to frontal cognitive areas (including BA 9/46 and the pre-SMA). Finally, activity during the maintenance phase in BA 9, anterior insula, pre-SMA and ventral dentate predicted subsequent accuracy of response to the probe during the retrieval phase. This finding underscored the significant contribution of the pre-SMA/ventral dentate pathway – observed several seconds prior to any motor response to the probe – to executive verbal working memory.

Classical conditioning paradigms, such as trace conditioning, in which a silent period elapses between the offset of the conditioned stimulus (CS) and the delivery of the unconditioned stimulus (US), and delay conditioning, in which the CS and US coterminate, are widely used to study the neural substrates of associative learning. However, there are significant gaps in our knowledge of the neural systems underlying conditioning in humans. For example, evidence from animal and human patient research suggests that the hippocampus plays a critical role during trace eyeblink conditioning, but there is no evidence to date in humans that the hippocampus is active during trace eyeblink conditioning or is differentially responsive to delay and trace paradigms. The present work provides a direct comparison of the neural correlates of human delay and trace eyeblink conditioning by using functional MRI. Behavioral results showed that humans can learn both delay and trace conditioning in parallel. Comparable delay and trace activation was measured in the cerebellum, whereas greater hippocampal activity was detected during trace compared with delay conditioning. These findings further support the position that the cerebellum is involved in both delay and trace eyeblink conditioning whereas the hippocampus is critical for trace eyeblink conditioning. These results also suggest that the neural circuitry supporting delay and trace eyeblink classical conditioning in humans and laboratory animals may be functionally similar.

Previous functional magnetic resonance imaging and patient studies indicate cerebellar participation in verbal working memory. In particular, event-related functional magnetic resonance imaging showed superior cerebellar activation during the initial encoding phase of the Sternberg task. This study used functional magnetic resonance imaging-guided transcranial magnetic stimulation (TMS) to test whether disruption of the right superior cerebellum (hemispheric lobule VI/Crus I) impairs verbal working memory performance. Single-pulse TMS was administered immediately after letter presentation during the encoding phase on half the trials. Sham TMS and a Motor Control task were included to test for general distraction and nonmemory-related motor effects. Results showed no effects of TMS on accuracy, but reaction times (RTs) on correct trials were significantly increased on TMS relative to non-TMS trials for the Verbal Working Memory and Motor Control tasks. Additional analyses showed that the increased RT was significantly greater for Verbal Working Memory than for the motor task, suggesting that the effect on working memory was not caused by interference with finger responses. Sham TMS did not affect RTs, indicating that the potentially distracting effects of the postencoding click did not contribute to the increase in RT. The observed effects from cerebellar disruption are consistent with proposed cerebrocerebellar involvement in verbal working memory.

Previous investigations have demonstrated that two regions in the right cerebellum, one located superiorly in hemispheral lobule VI/Crus I and another located inferiorly in hemispheral lobule VIIB/VIIIA, are activated during verbal working memory performance. On the basis of functional neuroimaging patterns of activation, as well as known cortico-pontine and ponto-cerebellar projections, the superior region has been hypothesized to contribute to the articulatory control system of working memory whereas the inferior region has been linked to the phonological store. The present study used event-related fMRI and individual estimates of hemodynamic response for both the cerebellum and neocortex to test this model and characterize the task phase specific cerebro-cerebellar activations for a Sternberg verbal working memory task. Results demonstrated that the right superior cerebellum showed the strongest activation during the initial encoding phase of the task, and, consistent with predictions, a similar pattern was observed in left opercular inferior frontal and premotor regions. In contrast, the right inferior cerebellum exhibited the greatest activation during the maintenance phase of the task, and as predicted, corresponded with activation in the left inferior parietal lobule. The significance of the results with respect to cerebro-cerebellar models of verbal working memory and to theoretical accounts of cerebellar involvement in cognition is discussed.

Converging evidence has implicated the cerebellum in verbal working memory. The current fMRI study sought to further characterize cerebrocerebellar participation in this cognitive process by revealing regions of activation common to a verbal working task and an articulatory control task, as well as regions that are uniquely activated by working memory. Consistent with our model's predictions, load-dependent activations were observed in Broca's area (BA 44/6) and the superior cerebellar hemisphere (VI/CrusI) for both working memory and motoric rehearsal. In contrast, activations unique to verbal working memory were found in the inferior parietal lobule (BA 40) and the right inferior cerebellum hemisphere (VIIB). These findings provide evidence for two cerebrocerebellar networks for verbal working memory: a frontal/superior cerebellar articulatory control system and a parietal/inferior cerebellar phonological storage system.

Although there is clear evidence of alcoholism-related damage to the frontal lobes and cerebellum from neuroimaging, neuropathological, and neuropsychological studies, the functional role of the cerebellum and cerebrocerebellar circuits related to verbal working memory deficits of alcoholics have not been well studied. Alcoholic and nonalcoholic subjects performed a Sternberg verbal working memory task while receiving an fMRI scan in a 3T magnet. This task has been found in previous studies to reliably activate the articulatory control and phonological storage components of the phonological loop (left frontal, left temporal/parietal structures, right superior cerebellar regions) in young healthy controls. We hypothesized that the alcoholics would show a different pattern of activation from the controls, based on the regions of interest (ROIs) identified from a previous study of healthy subjects. Behavioral results showed the alcoholics to be performing at a comparable level to the matched controls in terms of accuracy and median reaction time, with no statistically significant differences. However, analysis of the functional data revealed that the alcoholics exhibited greater activation in the left frontal (BA44/45) and right superior cerebellum (HVI) regions relative to the matched controls. These findings suggest that brain activation in left frontal and right cerebellar regions that support the articulatory control system of verbal working memory may require a compensatory increase in alcoholics in order to maintain the same level of performance as controls.

Declarative memory declines with age, but there is profound variation in the severity of this decline. Healthy elderly adults with high or low memory scores and young adults viewed words under semantic or non-semantic encoding conditions while undergoing fMRI. Young adults had superior memory for the words, and elderly adults with high memory scores had better memory for the words than those with low memory scores. The elderly with high scores had left lateral and medial prefrontal activations for semantic encoding equal to the young, and greater right prefrontal activation than the young. The elderly with low scores had reduced activations in all three regions relative to the elderly with high memory scores. Thus, successful aging was characterized by preserved left prefrontal and enhanced right prefrontal activation that may have provided compensatory encoding resources.

Functional magnetic resonance imaging has emerged as a powerful tool for mapping the neurologic underpinnings of sensory, motor and cognitive function. Much of this evolution carries assumptions about the subject population under study and, in particular, the neurologic status of subjects entered into studies either as healthy controls or as belonging to a specific disease group. Recent reports of incidental MRI abnormalities in normal volunteers for fMRI studies have brought to attention a variety of practical challenges and ethical dilemmas for researchers, many of whom are not physicians and most of whom have no formal radiological training. We propose a minimum standard for consenting subjects in fMRI protocols, and consider strategies over the longer term that call for expert physician participation, archiving of incidental findings including false positives, and the adoption of guidelines for handling variation in neural activations or performance that appear outside expected norms.

The ability of functional magnetic resonance imaging (fMRI) to localize activations in a single patient, along with the safety and widespread availability of this methodology, has lead to an increasing use of fMRI for clinical purposes such as pre-surgical planning. As methodology continues to improve and more experience with fMRI in the clinical setting is acquired, clinical functional neuroimaging will likely have an increasing influence over patient care. Therefore, ethical use of fMRI, as with other medical techniques, requires understanding the factors impacting the interpretation of the methodology. Issues affecting the validity and interpretation of clinical functional neuroimaging, including effects of altered hemodynamic response function, head motion, and structural changes in the brain, are reviewed. The distinction between correlated and necessary activation in a clinical context is discussed. Different types of statistical errors in fMRI analysis are described, along with their consequences to the patient. Finally, for the future of clinical fMRI development, the need for normative patient data, as well as standardized tasks, scan protocols, and data analyses, is discussed.

Psychological studies have found better memory in women than men for emotional events, but the neural basis for this difference is unknown. We used event-related functional MRI to assess whether sex differences in memory for emotional stimuli is associated with activation of different neural systems in men and women. Brain activation in 12 men and 12 women was recorded while they rated their experience of emotional arousal in response to neutral and emotionally negative pictures. In a recognition memory test 3 weeks after scanning, highly emotional pictures were remembered best, and remembered better by women than by men. Men and women activated different neural circuits to encode stimuli effectively into memory even when the analysis was restricted to pictures rated equally arousing by both groups. Men activated significantly more structures than women in a network that included the right amygdala, whereas women activated significantly fewer structures in a network that included the left amygdala. Women had significantly more brain regions where activation correlated with both ongoing evaluation of emotional experience and with subsequent memory for the most emotionally arousing pictures. Greater overlap in brain regions sensitive to current emotion and contributing to subsequent memory may be a neural mechanism for emotions to enhance memory more powerfully in women than in men.

Despite the brain's central role in sexual function, little is known about relationships between brain activation and sexual response. In this study, we employed functional MRI (fMRI) to examine relationships between brain activation and sexual arousal in a group of young, healthy, heterosexual males. Each subject was exposed to two sequences of video material consisting of explicitly erotic (E), relaxing (R) and sports (S) segments in an unpredictable order. Data on penile turgidity was collected using a custom-built pneumatic pressure cuff. Both traditional block analyses using contrasts between sexually arousing and non-arousing video clips and a regression using penile turgidity as the covariate of interest were performed. In both types of analyses, contrast images were computed for each subject and these images were subsequently used in a random effects analysis. Strong activations specifically associated with penile turgidity were observed in the right subinsular region including the claustrum, left caudate and putamen, right middle occipital/ middle temporal gyri, bilateral cingulate gyrus and right sensorimotor and pre-motor regions. Smaller, but significant activation was observed in the right hypothalamus. Few significant activations were found in the block analyses. Implications of the findings are discussed. Our study demonstrates the feasibility of examining brain activation/sexual response relationships in an fMRI environment and reveals a number of brain structures whose activation is time-locked to sexual arousal.

Functional magnetic resonance imaging (fMRI) was used to examine whether neural pathways used to encode pictures into memory were re-activated during retrieval of those memories. At encoding, subjects semantically classified common objects presented as pictures or words. At retrieval, subjects performed yes/no recognition memory judgments on words that had been encoded as pictures or as words. The retrieval test probed memory for the encoded item, but not memory for the modality of the encoded item (picture/word). Results revealed that a subset of the brain regions involved specifically in encoding of pictures were also engaged during recognition memory for the encoded pictures. Specifically, encoding of pictures relative to words engaged bilateral extrastriate visual cortex, namely fusiform, lingual, middle occipital, and inferior temporal gyri (Broadman area (BA) 18/19/37). Recognition memory judgments about words that were encoded as pictures relative to those that were encoded as words activated fusiform and inferior temporal gyri primarily in the left hemisphere. Thus, cortical areas originally involved in perception of a visual experience become part of the long-term memory trace for that experience. These findings suggest a neural basis for encoding specificity and transfer appropriate processing in human memory.

Writing is a uniquely human skill that we utilize nearly everyday. Lesion studies in patients with Gerstmann's syndrome have pointed to the parietal cortex as being critical for writing. Very little information is, however, available about the precise anatomical location of brain regions subserving writing in normal healthy individuals. In this study, we used functional magnetic resonance imaging (fMRI) to investigate parietal lobe function during writing to dictation. Significant clusters of activation were observed in left superior parietal lobe (SPL) and the dorsal aspects of the inferior parietal cortex (IPC) bordering the SPL. Localized clusters of activation were also observed in the left premotor cortex, sensorimotor cortex and supplementary motor area. No activation cluster was observed in the right hemisphere. These results clearly indicate that writing appears to be primarily organized in the language-dominant hemisphere. Further analysis revealed that within the parietal cortex, activation was significantly greater in the left SPL, compared to left IPC. Together with lesion studies, findings from the present study provide further evidence for the essential role of the left SPL in writing. Deficits to the precise left hemisphere parietal cortex regions identified in the present study may specifically underlie disorders of writing observed in Gerstmann's syndrome and apractic agraphia.

Functional imaging studies have examined which brain regions respond to emotional stimuli, but they have not determined how stable personality traits moderate such brain activation. Two personality traits, extraversion and neuroticism, are strongly associated with emotional experience and may thus moderate brain reactivity to emotional stimuli. The present study used functional magnetic resonance imaging to directly test whether individual differences in brain reactivity to emotional stimuli are correlated with extraversion and neuroticism in healthy women. Extraversion was correlated with brain reactivity to positive stimuli in localized brain regions, and neuroticism was correlated with brain reactivity to negative stimuli in localized brain regions. This study provides direct evidence that personality is associated with brain reactivity to emotional stimuli and identifies both common and distinct brain regions where such modulation takes place. Despite a strong scientific interest in the topic of emotions and the brain in the late 19th century (Darwin, 1872; James, 1884), a broad experimental effort to understand the neural basis of emotion did not commence until the last quarter of the 20th century. Inspired by animal studies investigating the role of the amygdala in

Paradoxically, attempts to visualize odorant-induced functional magnetic resonance imaging (fMRI) activation in the human have yielded activations in secondary olfactory regions but not in the primary olfactory cortex-piriform cortex. We show that odorant-induced activation in primary olfactory cortex was not previously made evident with fMRI because of the unique time course of activity in this region: in primary olfactory cortex, odorants induced a strong early transient increase in signal amplitude that then habituated within 30–40 s of odorant presence. This time course of activation seen here in the primary olfactory cortex of the human is almost identical to that recorded electrophysiologically in the piriform cortex of the rat. Mapping activation with analyses that are sensitive to both this transient increase in signal amplitude, and temporal-variance, enabled us to use fMRI to consistently visualize odorant-induced activation in the human primary olfactory cortex. The combination of continued accurate odorant detection at the behavioral level despite primary olfactory cortex habituation at the physiological level suggests that the functional neuroanatomy of the olfactory response may change throughout prolonged olfactory stimulation.

EEG and behavioural evidence suggests that air-borne chemicals can affect the nervous system without being consciously detected. EEG and behaviour, however, do not specify which brain structures are involved in chemical sensing that occurs below a threshold of conscious detection. Here we used functional MRI to localize brain activation induced by high and low concentrations of the air-borne compound oestra-1,3,5(10),16-tetraen-3yl acetate. Following presentations of both concentrations, eight of eight subjects reported verbally that they could not detect any odour (P = 0.004). Forced choice detection performed during the presentations revealed above-chance detection of the high concentration, but no better than chance detection of the low concentration compound. Both concentrations induced significant brain activation, primarily in the anterior medial thalamus and inferior frontal gyrus. Activation in the inferior frontal gyrus during the high concentration condition was significantly greater in the right than in the left hemisphere (P = 0.03). A trend towards greater thalamic activation was observed for the high concentration than the low concentration compound (P = 0.08). These findings localize human brain activation that was induced by an undetectable air-borne chemical (the low concentration compound).

Functional magnetic resonance imaging was used to test whether odorants induce activation in the cerebellum of the human. The odorants vanillin and propionic acid both induced significant activation, primarily in the posterior lateral hemispheres. Activation was concentration-dependent, greater after stimulation with higher concentration odorants. By contrast, the action of sniffing nonodorized air induced significant activation in the anterior cerebellum, primarily in the central lobule. These findings demonstrate that the cerebellum plays a role in human olfaction. A hypothesis is proposed whereby the cerebellum maintains a feedback mechanism that regulates sniff volume in relation to odor concentration.

Functional neuroimaging studies of episodic recognition memory consistently demonstrate retrieval-associated activation in right prefrontal regions, including the right anterior and right dorsolateral prefrontal cortices. In theory, these activations could reflect processes associated with retrieval success, retrieval effort or retrieval attempt; each of these hypotheses has some support from previous studies. In Experiment 1, we examined these functional interpretations using functional MRI to measure prefrontal activation across multiple levels of recognition performance. Results revealed similar patterns of right prefrontal activation across varying levels of retrieval success and retrieval effort, suggesting that these activations reflect retrieval attempt. Retrieval attempt may include initiation of retrieval search or evaluation of the products of retrieval, such as scrutiny of specific attributes of the test item in an effort to determine whether it was encountered previously. In Experiment 2, we examined whether engagement of retrieval attempt is context-dependent by varying the context in which retrieval was performed; this was done by changing test instructions. Importantly, study and test stimuli were held constant, with only the test instructions varying across conditions. Results revealed that the pattern of right prefrontal activation varied across retrieval contexts. Collectively, these experiments suggest that right prefrontal regions mediate processes associated with retrieval attempt, with the probability of engaging these regions depending upon the retrieval context. Conflicting results across previous studies may be reconciled if the influence of retrieval context on the adopted retrieval strategy is considered. Finally, these results suggest that right prefrontal regions activated during recognition are not critical for successful performance as similar magnitudes of activation were present across multiple levels of performance. These findings reconcile imaging results with the selective effects of prefrontal lesions on retrieval-intensive episodic memory tests.

Current brain models of emotion processing hypothesize that positive (or approach-related) emotions are lateralized towards the left hemisphere, whereas negative (or withdrawal-related) emotions are lateralized towards the right hemisphere. Brain imaging studies, however, have so far failed to document such hemispheric lateralization. In a functional magnetic resonance imaging (fMRI) study, 14 female subjects viewed alternating blocks of emotionally valenced positive and negative pictures. When the experience of valence was equated for arousal, overall brain reactivity was lateralized towards the left hemisphere for positive pictures and towards the right hemisphere for negative pictures. This study provides direct support for the valence hypothesis, under conditions of equivalent arousal, by means of functional brain imaging.

Human brain imaging studies have found that increases in functional activation in left-frontal cortex during cognitive tasks are often accompanied by similar increases in right-cerebellar regions. The present study used functional magnetic resonance imaging (fMRI) to investigate the distinctive contributions of these regions using a word stem completion task. Stems with many possible completions (MANY condition) were alternately presented with stems that had few possible completions (FEW condition), and subjects were asked to covertly complete each stem with a word and press a response switch for each successful completion. Prominent increases in activation in the MANY, relative to the FEW, condition were observed in the left middle frontal gyrus (Brodmann areas 9/10) and left caudate nucleus. In contrast, portions of the right-cerebellar hemisphere (posterior quadrangular lobule and superior semilunar lobule) and cerebellar vermis exhibited increases in the FEW, relative to the MANY, condition. This double dissociation suggests that the frontal and cerebellar regions make distinctive contributions to cognitive performance, with left-frontal (and striatal) activations reflecting response selection, which increases in difficulty when there are many appropriate responses, and right-cerebellar activation reflecting the search for responses, which increases in difficulty when even a single appropriate response is hard to retrieve.

The sensation and perception of smell (olfaction) are largely dependent on sniffing, which is an active stage of stimulus transport and therefore an integral component of mammalian olfaction1,2. Electrophysiological data obtained from study of the hedgehog, rat, rabbit, dog and monkey indicate that sniffing (whether or not an odorant is present) induces an oscillation of activity in the olfactory bulb, driving the piriform cortex in the temporal lobe, in other words, the piriform is driven by the olfactory bulb at the frequency of sniffing3,4,5,6. Here we use functional magnetic resonance imaging (fMRI) that is dependent on the level of oxygen in the blood to determine whether sniffing can induce activation in the piriform of humans, and whether this activation can be differentiated from activation induced by an odorant. We find that sniffing, whether odorant is present or absent, induces activation primarily in the piriform cortex of the temporal lobe and in the medial and posterior orbito-frontal gyri of the frontal lobe. The source of the sniff-induced activation is the somatosensory stimulation that is induced by air flow through the nostrils. In contrast, a smell, regardless of sniffing, induces activation mainly in the lateral and anterior orbito-frontal gyri of the frontal lobe. The dissociation between regions activated by olfactory exploration (sniffing) and regions activated by olfactory content (smell) shows a distinction in brain organization in terms of human olfaction.

The learning of perceptual skills is thought to rely upon multiple regions in the cerebral cortex, but imaging studies have not yet provided evidence about the changes in neural activity that accompany visual skill learning. Functional magnetic resonance imaging (fMRI) was used to examine changes in activation of posterior brain regions associated with the acquisition of mirror-reading skill for novel and practiced stimuli. Multiple regions in the occipital lobe, inferior temporal cortex, superior parietal cortex and cerebellum were involved in the reading of mirror-reversed compared to normally oriented text. For novel stimuli, skilled mirror-reading was associated with decreased activation in the right superior parietal cortex and posterior occipital regions and increased activation in the left inferior temporal lobe. These results suggest that learning to read mirror-reversed text involves a progression from visuospatial transformation to direct recognition of transformed letters. Reading practiced, relative to unpracticed, stimuli was associated with decreased activation in occipital visual cortices, inferior temporal cortex and superior parietal cortex and increased activation in occipito-parietal and lateral temporal regions. By examining skill learning and item-specific repetition priming in the same task, this study demonstrates that both of these forms of learning exhibit shifts in the set of neural structures that contribute to performance.

The lobular distributions of functional activation of the cerebellum during verbal working-memory and finger movement tasks were investigated using functional magnetic resonance imaging (fMRI). Relative to a rest control, finger tapping of the right hand produced ipsilateral-increased activation in HIV/HV [Roman numeral designations based on Larsell’s (Larsell and Jansen, 1972) nomenclature] and HVI and weaker activation in HVIII that was stronger on the ipsilateral side. For a working-memory task, subjects were asked to remember six (high load) or one (low load) visually presented letters across a brief delay. To assess the motoric aspects of rehearsal in the absence of working memory, we asked the subjects to repeatedly read subvocally six or one letters at a rate that approximated the internally generated rehearsal of working memory (motoric rehearsal task). For both tasks, bilateral regions of the superior cerebellar hemispheres (left superior HVIIA and right HVI) and portions of posterior vermis (VI and superior VIIA) exhibited increased activation during high relative to low load conditions. In contrast, the right inferior cerebellar hemisphere (HVIIB) exhibited this load effect only during the working-memory task. We hypothesize that HVI and superior HVIIA activation represents input from the articulatory control system of working memory from the frontal lobes and that HVIIB activation is derived from the phonological store in temporal and parietal regions. From these inputs, the cerebellum could compute the discrepancy between actual and intended phonological rehearsal and use this information to update a feedforward command to the frontal lobes, thereby facilitating the phonological loop.

We examined brain activation, as measured by functional magnetic resonance imaging, during problem solving in seven young, healthy participants. Participants solved problems selected from the Raven's Progressive Matrices Test, a test known to predict performance on a wide range of reasoning tasks. In three conditions, participants solved problems requiring (1) analytic reasoning; (2) figural or visuospatial reasoning; or (3) simple pattern matching that served as a perceptual-motor control. Right frontal and bilateral parietal regions were activated more by figural than control problems. Bilateral frontal and left parietal, occipital, and temporal regions were activated more by analytic than figural problems. All of these regions were activated more by analytic than match problems. Many of these activations occurred in regions associated with working memory. Figural reasoning activated areas involved in spatial and object working memory. Analytic reasoning activated additional areas involved in verbal working memory and domain-independent associative and executive processes. These results suggest that fluid reasoning is mediated by a composite of working memory systems.

A brain image averaging technique was applied to three-dimensional magnetic resonance images to identify visually detectable brain volume abnormalities in chronically alcoholic men, compared with healthy control men. This technique, which was based on pixel-by-pixel statistical probability mapping, revealed a dramatic reduction in the area of the corpus callosum in older alcoholics (age 45 years or older), relative to age-matched controls. Subsequent analysis used anatomical landmarks to outline the borders of midsagittal sections of the corpus callosum in a larger group of alcoholics and controls, who spanned the adult age range from 23 to 71 years. This analysis revealed significant reduction, most prominent in the genu and body, of total callosal area in the alcoholic group relative to the control group; the results were the same whether raw area measures or head size plus age adjusted measure were analyzed. Significant thinning of the callosal body in alcoholics is usually attributed to the relatively rare, nutritional-deficient condition, Marchiafava-Bignami disease. However, callosal thinning was present in vivo in chronic alcoholics without clinical symptoms of severe liver disease, amnesia, or alcoholic dementia. These data suggest that chronic alcoholism can be characterized by a continuum of graded brain dysmorphology, rather than classical alcoholic-related subsyndromes, such as Marchiafava-Bignami disease.

Prefrontal cortical function was examined during semantic encoding and repetition priming using functional magnetic resonance imaging (fMRI), a noninvasive technique for localizing regional changes in blood oxygenation, a correlate of neural activity. Words studied in a semantic (deep) encoding condition were better remembered than words studied in both easier and more difficult nonsemantic (shallow) encoding conditions, with difficulty indexed by response time. The left inferior prefrontal cortex (LIPC) (Brodmann's areas 45, 46, 47) showed increased activation during semantic encoding relative to nonsemantic encoding regardless of the relative difficulty of the nonsemantic encoding task. Therefore, LIPC activation appears to be related to semantic encoding and not task difficulty. Semantic encoding decisions are performed faster the second time words are presented. This represents semantic repetition priming, a facilitation in semantic processing for previously encoded words that is not dependent on intentional recollection. The same LIPC area activated during semantic encoding showed decreased activation during repeated semantic encoding relative to initial semantic encoding of the same words. This decrease in activation during repeated encoding was process specific; it occurred when words were semantically reprocessed but not when words were nonsemantically reprocessed. The results were apparent in both individual and averaged functional maps. These findings suggest that the LIPC is part of a semantic executive system that contributes to the on-line retrieval of semantic information.

This paper describes a method for increasing the spatial detail of the EEG and for integrating physiological data with anatomical models based on magnetic resonance images (MRIs). This method includes techniques to efficiently record EEG data from up to 124 channels, to measure 3-D electrode positions for alignment with MRI-derived head models, and to estimate potentials near the outer convexity of the cortex using a spatial deblurring technique which uses a realistic model of the structure of the head and which makes no assumptions about the number or type of generator sources. The validity of this approach has been initially tested by comparing estimated cortical potentials with those measured with subdural grid recordings from two neurosurgical patients. The method is illustrated with somatosensory steady-state evoked potential data recorded from 5 healthy subjects. Results suggest that deblurred 124-channel topographic maps, registered with a subject's MRI and rendered in 3 dimensions, provide better spatial detail than has heretofore been obtained with scalp EEG recordings. The results also suggest that the potential for EEG as a functional neuroimaging modality has yet to be fully realized.

Speech—both overt and covert—facilitates working memory by creating and refreshing motor memory traces, allowing new information to be received and processed. Neuroimaging studies suggest a functional topography within the sub-regions of the cerebellum that subserve verbal working memory. Medial regions of the anterior cerebellum support overt speech, consistent with other forms of motor execution such as finger tapping, whereas lateral portions of the superior cerebellum support speech planning and preparation (e.g., covert speech). The inferior cerebellum is active when information is maintained across a delay, but activation appears to be independent of speech, lateralized by modality of stimulus presentation, and possibly related to phonological storage processes. Motor (dorsal) and cognitive (ventral) channels of cerebellar output nuclei can be distinguished in working memory. Clinical investigations suggest that hyper-activity of cerebellum and disrupted control of inner speech may contribute to certain psychiatric symptoms.

This study was designed to investigate cerebellar lobular contributions to specific cognitive deficits observed after cerebellar tumor resection. Verbal working memory (VWM) tasks were administered to children following surgical resection of cerebellar pilocytic astrocytomas and age-matched controls. Anatomical MRI scans were used to quantify the extent of cerebellar lobular damage from each patient's resection. Patients exhibited significantly reduced digit span for auditory but not visual stimuli, relative to controls, and damage to left hemispheral lobule VIII was significantly correlated with this deficit. Patients also showed reduced effects of articulatory suppression and this was correlated with damage to the vermis and hemispheral lobule IV/V bilaterally. Phonological similarity and recency effects did not differ overall between patients and controls, but outlier patients with abnormal phonological similarity effects to either auditory or visual stimuli were found to have damage to hemispheral lobule VIII/VIIB on the left and right, respectively. We postulate that damage to left hemispheral lobule VIII may interfere with encoding of auditory stimuli into the phonological store. These data corroborate neuroimaging studies showing focal cerebellar activation during VWM paradigms, and thereby allow us to predict with greater accuracy which specific neurocognitive processes will be affected by a cerebellar tumor resection.

Lack of sexual interest is the most common sexual complaint among women. However, factors affecting sexual desire in women have rarely been studied. While the role of the brain in integrating the sensory, attentional, motivational, and motor aspects of sexual response is commonly acknowledged as important, little is known about specific patterns of brain activation and sexual interest or response, particularly among women. We compared 20 females with no history of sexual dysfunction (NHSD) to 16 women with hypoactive sexual desire disorder (HSDD) in a functional magnetic resonance imaging (fMRI) study that included assessment of subjective sexual arousal, peripheral sexual response using a vaginal photoplethysmograph (VPP), as well as brain activation across three time points. Video stimuli included erotic, sports, and relaxing segments. Subjective arousal to erotic stimuli was significantly greater in NHSD participants compared with HSDD. In the erotic-sports contrast, NHSD women showed significantly greater activation in the bilateral entorhinal cortex than HSDD women. In the same contrast, HSDD females demonstrated higher activation than NHSD females in the medial frontal gyrus (Brodmann area (BA) 10), right inferior frontal gyrus (BA 47) and bilateral putamen. There were no between group differences in VPP-correlated brain activation and peripheral sexual response was not significantly associated with either subjective sexual response or brain activation patterns. Findings were consistent across the three experimental sessions. The results suggest differences between women with NHSD and HSDD in encoding arousing stimuli, retrieval of past erotic experiences, or both. The findings of greater activation in BA 10 and BA 47 among women with HSDD suggest that this group allocated significantly more attention to monitoring and/or evaluating their responses than NHSD participants, which may interfere with normal sexual response.

Phonologically similar items (mell, rell, gell) are more difficult to remember than dissimilar items (shen, floy, stap), likely because of mutual interference of the items in the phonological store. Low-frequency transcranial magnetic stimulation (TMS), guided by functional magnetic resonance imaging (fMRI) was used to disrupt this phonological confusion by stimulation of the left inferior parietal (LIP) lobule. Subjects received TMS or placebo stimulation while remembering sets of phonologically similar or dissimilar pseudo-words. Consistent with behavioral performance of patients with neurological damage, memory for phonologically similar, but not dissimilar, items was enhanced following TMS relative to placebo stimulation. Stimulation of a control region of the brain did not produce any changes in memory performance. These results provide new insights into how the brain processes verbal information by establishing the necessity of the inferior parietal region for optimal phonological storage. A mechanism is proposed for how TMS reduces phonological confusion and leads to facilitation of phonological memory.

The participation of medial temporal-lobe structures in memory performance was examined by functional magnetic resonance imaging of local blood oxygenation level–dependent signals. Signals were measured during encoding into memory complex scenes or line drawings and during retrieval from memory of previously studied line drawings or words. Encoding tasks yielded increased signals for unfamiliar information in a posterior medial-temporal region that were focused in the parahippocampal cortex. Retrieval tasks yielded increased signals for successfully remembered information in an anterior medial-temporal region that were focused in the subiculum. These results indicate that separate components of the human medial temporal-lobe memory system are active during distinct memory processes.

Load-dependent and practice-related changes in neocortical and cerebellar structures involved in verbal working memory (VWM) were investigated using functional MRI (fMRI) and a two alternative forced choice Sternberg paradigm. Using working memory loads ranging from 2 to 6 letters, regions exhibiting linear and quadratic trends in load-dependent activations were identified. Behaviorally, reaction time measurements revealed significant linear increases with increasing memory load, and significant decreases with increased task practice. Brain activations indicated a preponderance of linear load-dependent responses in both superior (lobule VI/Crus I) and inferior (lobule VIIB/VIIIA) cerebellar hemispheres, as well as in areas of neocortex including left precentral (BA 6), inferior frontal (BA 47), parahippocampal (BA 35), inferior parietal (BA 40), cingulate (BA 32), and right inferior and middle frontal (BA 46/47) regions. Fewer voxels exhibited quadratic without linear trends with the most prominent of these activations located in left inferior parietal (BA 40), precuneus, and parahippocampal regions. Analysis of load x session interactions revealed that right inferior cerebellar and left inferior parietal activations increased with practice, as did the correlations between activation in each region with reaction time, suggesting that changes in this cerebro-cerebellar network underlie practice-related increases in efficiency of VWM performance. These results replicate and extend our previous findings of fMRI activation in the cerebellum during VWM, and demonstrate predominately linear increases in cerebro-cerebellar activation with increasing memory load as well as changes in network function with increased task proficiency.

Estimation of statistical power in functional MRI (fMRI) requires knowledge of the expected percent signal change between two conditions as well as estimates of the variability in percent signal change. Variability can be divided into intra-subject variability, reflecting noise within the time series, and inter-subject variability, reflecting subject-to-subject differences in activation. The purpose of this study was to obtain estimates of percent signal change and the two sources of variability from fMRI data, and then use these parameter estimates in simulation experiments in order to generate power curves. Of interest from these simulations were conclusions concerning how many subjects are needed and how many time points within a scan are optimal in an fMRI study of cognitive function. Intra-subject variability was estimated from resting conditions, and inter-subject variability and percent signal change were estimated from verbal working memory data. Simulations derived from these parameters illustrate how percent signal change, intra- and inter-subject variability, and number of time points affect power. An empirical test experiment, using fMRI data acquired during somatosensory stimulation, showed good correspondence between the simulation-based power predictions and the power observed within somatosensory regions of interest. Our analyses suggested that for a liberal threshold of 0.05, about 12 subjects were required to achieve 80% power at the single voxel level for typical activations. At more realistic thresholds, that approach those used after correcting for multiple comparisons, the number of subjects doubled to maintain this level of power.