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Transcranial ultrasound holds much potential as a safe, non-invasive modality for navigated neuromodulation, with low-intensity focused ultrasound (FUS) and transcranial pulse stimulation (TPS) representing the two main modalities. While neuroscientific and preclinical applications have received much interest, clinical applications are still relatively scarce. For safety considerations, the current literature is largely based on guidelines for ultrasound imaging that uses various physical parameters to describe the ultrasound pulse form and expected bioeffects. However, the safety situation for neuromodulation is inherently different. This article provides an overview of relevant ultrasound parameters with a focus on bioeffects relevant for safe clinical applications. Further, a retrospective analysis of safety data for clinical TPS applications in patients is presented.

Background Photophobia, the aberrantly increased sensitivity to light, is a common symptom in migraine patients and light discomfort is frequently found as a trigger for migraine attacks. In behavioral studies, planned exposure to light was found to reduce headache in migraine patients with photophobia, potentially by increasing habituation to this migraine trigger. Here, we aimed to elucidate neurophysiological mechanisms of light exposure versus light deprivation in migraine patients using functional magnetic resonance imaging (fMRI). Methods Ten migraine patients (9 female, age = 28.70 ± 8.18 years) and 11 healthy controls (9 female, age = 23.73 ± 2.24 years) spent one hour on 7 consecutive days exposed to flashing light (Flash) or darkness (Dark) using a crossover design with a wash-out period of 3 months. Study participants kept a diary including items on interictal and ictal photophobia, presence and severity of headache 7 days before, during and 7 days after the interventions. One week before and one day after both interventions, fMRI using flickering light in a block design was applied. Functional activation was analyzed at whole-brain level and habituation of the visual cortex (V1) was modeled with the initial amplitude estimate and the corrected habituation slope. Results Mean interictal photophobia decreased after both interventions, but differences relative to the baseline did not survive correction for multiple comparisons. At baseline, flickering light induced activation in V1 was higher in the patients compared to the controls, but activation normalized after the Flash and the Dark interventions. V1 habituation indices correlated with headache frequency, headache severity and ictal photophobia. In the Flash condition, the individual change of headache frequency relative to the baseline corresponded almost perfectly to the change of the habituation slope compared to the baseline. Conclusions On average, light exposure did not lead to symptom relief, potentially due to the short duration of the intervention and the high variability of the patients’ responses to the intervention. However, the strong relationship between visual cortex habituation and headache symptoms and its modulation by light exposure might shed light on the neurophysiological basis of exposure treatment effects. Trial registration NCT05369910 (05/06/2022, retrospectively registered).

The Austrian Prehospital Stroke Scale (APSS) score was developed to predict large vessel occlusion (LVO) and improve prehospital transportation triage. Its accuracy has been previously analyzed retrospectively. We now aimed to investigate the accuracy, as well as the impact of the implementation of a triage strategy using this score on treatment times and outcome in a prospective study.Prospective diagnostic test accuracy and before-after interventional study. EMS prospectively evaluated APSS in patients suspected of stroke. Accuracy was compared with other LVO scores. Patients with APSS ≥4 points were brought directly to the comprehensive stroke center. Treatment time frames, neurological, and radiological outcome before and after the APSS implementation were compared.A total of 307 patients with suspected stroke were included from October 2018 to February 2020. Treatable LVO was present in 79 (26%). Sensitivity of APSS to detect those was 90%, specificity 79%, positive predictive value 66%, negative predictive value 95%, and area under the curve 0.87 (95% CI 0.83-0.91). This was similar to in-hospital NIHSS (AUC 0.89 95% CI 0.89-0.92, p = .06) and superior to CPSS (AUC 0.83 95% CI 0.78-0.87, p = .01). Implementation of APSS triage increased direct transportation rate for LVO patients (21% before vs. 52% after; p .001) with a significant time benefit (alert to groin puncture time benefit: 51 min (95% CI 28-74; p .001). Neurological and radiological outcome did not differ significantly.Austrian Prehospital Stroke Scale triage showed an accuracy comparable with in-hospital NIHSS, and lead to a significant optimization of prehospital workflows in patients with potential LVO.

After cardiac arrest (CA), some patients report impressions with highly realistic features, often referred to as near-death experience (NDE). The frequency of such episodes seems to be variable, with various types of content. In a prospective study, we subjected 126 CA cases treated at the Department of Emergency Medicine of the Medical University of Vienna under carefully controlled conditions to a structured interview. We included all patients admitted due to CA, whose communicative abilities were restored and who agreed to participate in the study. The questionnaire inquired as to living conditions, attitudes towards issues of life and death, and last recollections before and first impressions after the CA. The majority of the subjects (91 = 76%) replied to inquiries concerning impressions during CA with “nothing” or “blackout”, but 20 (16%) gave a detailed account. A German version of the Greyson questionnaire specifically addressing NDE phenomena (included towards the end of the interview) resulted in ≥7 points in five patients (4%). Three patients reported a meeting with deceased relatives (one with 6 Greyson points), one an out-of-body episode, and one having been sucked into a colorful tunnel. Eleven of these twenty cases had their cardiopulmonary resuscitation (CPR) started within the first min of CA, a higher fraction than cases without experience. Reported experience after CA was of high significance for the patients; many of them changed their point of view on issues of life and death.

Objectives: Prediction of large vessel occlusion (LVO) is highly relevant for accurate prehospital transportation triage. The Austrian Prehospital Stroke Scale (APSS) score for LVO prediction was d...

Transcranial pulse stimulation (TPS) has been recently introduced as a novel clinical brain stimulation technique based on highly focused ultrasound pressure pulses. In a first pilot study on clinical effects of navigated and focused ultrasound neuromodulation, a dichotomy of functional effects was found: patients with Alzheimer's disease improved cognition and language but deteriorated with visuo-constructive functions.We analyzed changes in functional connectivity measured with functional magnetic resonance imaging (fMRI) using graph analysis of a visuo-constructive network in 18 patients with Alzheimer's disease. We calculated the network's global efficiency and tested for correlation with visuo-constructive test scores to explain this dichotomy.Important visuo-constructive network nodes were not stimulated in the pilot setting and correspondingly global efficiency of a visuo-constructive network was decreased after TPS therapy, compatible with a natural progress of the disease. A correlation between visuo-constructive scores and changes in global efficiency was found.Results argue for a high functional specificity of ultrasound-based neuromodulation with TPS.Over the last decade, there has been growing interest in ultrasound-based non-invasive brain stimulation techniques in neuroscience and as a potential therapy for disorders of the brain. Transcranial pulse stimulation (TPS) has been introduced as an innovative neuromodulation technique, applying ultrashort pressure pulses through the skull into neural tissue with 3D navigation in real time. In the first clinical pilot study, patients suffering from Alzheimer’s disease showed an increase in memory and language functions for up to 3 months after TPS therapy. However, visuo-constructive capacities (e.g., copying a geometrical figure) worsened. Notably, brain areas relevant for such processes had been left out during stimulation. This begged the question whether the brain areas that were targeted for brain stimulation as well as functional changes could explain this diverse response pattern. We therefore analyzed functional magnetic resonance data from patients. Specifically, we compared graph theoretical functional connectivity measures in a visuo-constructive network before and after TPS therapy. We found a decrease in connectivity in a central network node, which also correlated with visuo-constructive test scores. This deterioration is likely associated with normal disease progression. Together with the already reported improvement in global cognitive functions, these results argue for a functional specific effect of TPS.

Background and purpose Unilateral neglect is a common cognitive disorder following stroke. Neglect has a significant impact on functional outcomes, so it is important to detect. However, there is no consensus on which are the best screening tests to administer to detect neglect in time-limited clinical environments. Methods Members of the European Academy of Neurology Scientific Panel on Higher Cortical Functions, neuropsychologists, occupational therapists, and researchers produced recommendations for primary and secondary tests for bedside neglect testing based on a rigorous literature review, data extraction, online consensus meeting, and subsequent iterations. Results A total of 512 articles were screened, and 42 were included. These reported data from 3367 stroke survivors assessed using 62 neglect screens. Tests were grouped into cancellation, line bisection, copying, reading/writing, and behavioral. Cancellation tasks were most frequently used (97.6% of studies), followed by bisection, copying, behavioral, and reading/writing assessments. The panel recommended a cancellation test as the primary screening test if there is time to administer only one test. One of several cancellation tests might be used, depending on availability. If time permits, one or more of line bisection, figure copying, and baking tray task were recommended as secondary tests. Finally, if a functional and ecological test is feasible, the Catherine Bergego Scale was recommended. Overall, the literature suggests that no single test on its own is sufficient to exclude a diagnosis of neglect. Therefore, the panel recommended that multiple neglect tests should be used whenever possible. Conclusions This study provides consensus recommendations for rapid bedside detection of neglect in real-world, clinical environments.

The ability to generate complex hierarchical structures is a crucial component of human cognition which can be expressed in the musical domain in the form of hierarchical melodic relations. The neural underpinnings of this ability have been investigated by comparing the perception of well-formed melodies with unexpected sequences of tones. However, these contrasts do not target specifically the representation of rules generating hierarchical structure. Here, we present a novel paradigm in which identical melodic sequences are generated in four steps, according to three different rules: The Recursive rule, generating new hierarchical levels at each step; The Iterative rule, adding tones within a fixed hierarchical level without generating new levels; and a control rule that simply repeats the third step. Using fMRI, we compared brain activity across these rules when participants are imagining the fourth step after listening to the third (generation phase), and when participants listened to a fourth step (test sound phase), either well-formed or a violation. We found that, in comparison with Repetition and Iteration, imagining the fourth step using the Recursive rule activated the superior temporal gyrus (STG). During the test sound phase, we found fronto-temporo-parietal activity and hippocampal de-activation when processing violations, but no differences between rules. STG activation during the generation phase suggests that generating new hierarchical levels from previous steps might rely on retrieving appropriate melodic hierarchy schemas. Previous findings highlighting the role of hippocampus and inferior frontal gyrus may reflect processing of unexpected melodic sequences, rather than hierarchy generation per se. Electronic supplementary material The online version of this article (10.1007/s00429-020-02105-7) contains supplementary material, which is available to authorized users.

Ultrasound-based brain stimulation is a novel, non-invasive therapeutic approach to precisely target regions of interest. Data from a first clinical trial of patients with Alzheimer's disease (AD) receiving 2-4 weeks transcranial pulse stimulation (TPS) have shown memory and cognitive improvements for up to 3 months, despite ongoing state-of-the-art treatment. Importantly, depressive symptoms also improved.We analyzed changes in Beck Depression Inventory (BDI-II) and functional connectivity (FC) changes with functional magnetic resonance imaging in 18 AD patients.We found significant improvement in BDI-II after TPS therapy. FC analysis showed a normalization of the FC between the salience network (right anterior insula) and the ventromedial network (left frontal orbital cortex).Stimulation of areas related to depression (including extended dorsolateral prefrontal cortex) appears to alleviate depressive symptoms and induces FC changes in AD patients. TPS may be a novel add-on therapy for depression in AD and as a neuropsychiatric diagnosis.

Autistic spectrum disorder (ASD) is a common developmental disorder in children. The latest non-intrusive brain stimulation (NIBS) technology—transcranial pulse stimulation (TPS)—has been proven effective in older adults with mild neurocognitive disorders and adults with major depressive disorder. Nonetheless, there is so far no robust randomized controlled trial (RCT) conducted on adolescents with ASD nationwide. This study proposes a two-armed (verum TPS group vs. sham TPS group), double-blinded, randomized, sham-controlled trial. Both groups will be measured at four timepoints, namely, baseline (T1), 2 weeks immediately after post-TPS intervention (T2), and at the 1-month (T3) and 3-month (T4) follow-ups. Thirty-four subjects, aged between 12 and 17, diagnosed with ASD will be recruited in this study. All subjects will be computerized randomised into the verum TPS group or the sham TPS group on a 1:1 ratio. All subjects will undertake functional MRI (fMRI) before and after the 2-weeks TPS interventions, which will be completed in 2 weeks’ time. This will be the first RCT evaluating the efficacy of TPS adolescents with ASD in Hong Kong. Clinical Trial Registration: ClinicalTrials.gov, identifier: NCT05408793.

Background With the high spatial resolution and the potential to reach deep brain structures, ultrasound-based brain stimulation techniques offer new opportunities to non-invasively treat neurological and psychiatric disorders. However, little is known about long-term effects of ultrasound-based brain stimulation. Applying a longitudinal design, we comprehensively investigated neuromodulation induced by ultrasound brain stimulation to provide first sham-controlled evidence of long-term effects on the human brain and behavior. Methods Twelve healthy participants received three sham and three verum sessions with transcranial pulse stimulation (TPS) focused on the cortical somatosensory representation of the right hand. One week before and after the sham and verum TPS applications, comprehensive structural and functional resting state MRI investigations and behavioral tests targeting tactile spatial discrimination and sensorimotor dexterity were performed. Results Compared to sham, global efficiency significantly increased within the cortical sensorimotor network after verum TPS, indicating an upregulation of the stimulated functional brain network. Axial diffusivity in left sensorimotor areas decreased after verum TPS, demonstrating an improved axonal status in the stimulated area. Conclusions TPS increased the functional and structural coupling within the stimulated left primary somatosensory cortex and adjacent sensorimotor areas up to one week after the last stimulation. These findings suggest that TPS induces neuroplastic changes that go beyond the spatial and temporal stimulation settings encouraging further clinical applications.

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSIMPORTANCEC_ST_ABSMelodic Intonation Therapy (MIT) is a prominent rehabilitation programme for individuals with post-stroke aphasia. Despite substantial progress in recent years, the efficacy of MIT remains not fully understood. OBJECTIVEBased on a-priori hypotheses, the present meta-analysis investigated the efficacy of MIT while considering quality of outcomes (psychometrically validated versus unvalidated measures), experimental design (presence versus absence of randomisation and control group), influence of spontaneous recovery (quantified as number of months post-stroke), MIT version applied (original versus modified protocol), and level of generalisation (performance on trained versus untrained items). DATA SOURCESAn extensive literature search in all major online databases, trials registers and the grey literature identified 606 studies (years searched: 1973-2021). STUDY SELECTIONInclusion criteria: randomised controlled trial (RCT) data or case reports on adults with aphasia; pre-post assessment of language performance. Exclusion criteria: substantial variation from original MIT protocol; unvalidated outcomes, unless both trained and untrained items were compared; essential information not indicated/retrievable. Final sample: 22 studies. DATA EXTRACTION AND SYNTHESISFollowing PRISMA guidelines, studies were double-coded. Multi-level mixed- and random-effects models were used to separately meta-analyse RCT and non-RCT data. MAIN OUTCOMES AND MEASURESMeasures of language performance focused on aphasia severity, everyday communication ability, domain-general function, language comprehension, non-communicative language expression, and speech-motor planning. RESULTSUnvalidated outcomes appeared to attenuate MITs effect size by a factor of 0.29-0.43 across study designs when compared to validated outcomes. Moreover, MITs effect size was 5.7 times larger for non-RCT data compared to RCT data. Effect size also decreased with number of months post-stroke, suggesting confound through spontaneous recovery primarily within the first year post-stroke. In contrast, variation of the original MIT protocol did not systematically alter benefit from treatment. Crucially, analyses demonstrated significantly improved performance on trained and untrained items. The latter finding arose mainly from gains in repetition tasks, rather than other domains of verbal expression including everyday communication ability. CONCLUSIONS AND RELEVANCEAccounting for various methodological aspects, the current results confirm the promising role of MIT in improving language performance on trained items and in repetition tasks, while highlighting possible limitations in promoting everyday communication ability. KO_SCPLOWEYC_SCPLOW PO_SCPLOWOINTSC_SCPLOWO_ST_ABSQUESTIONC_ST_ABSWhat determines the efficacy of Melodic Intonation Therapy (MIT), arguably the best-known treatment programme for individuals with neurological communication disorders? FINDINGSMITs effect size was modulated by the psychometric quality of outcomes, use of randomisation and control groups, and the number of months post-stroke at the time of testing. Language performance improved significantly on trained items, less for everyday communication ability on untrained items. MEANINGOur findings emphasise the importance of appropriate outcomes and rigorous study design to obtain realistic effect size estimates. While MIT promotes performance on trained items, it appears to have limited impact on everyday communication ability.

PURPOSE OF REVIEW Imaging constitutes one of the key pillars in the diagnostic workup after a first seizure as well as for the presurgical workup in epilepsy. The role of imaging in emergency situations, mainly to support the adequate diagnosis, as well as its role in planning of noninvasive image-guided therapies is less well established. Here, we provide an overview on peri-ictal imaging findings to support differential diagnosis in emergency situations and describe recent attempts toward minimal invasive therapy in the treatment of epilepsy and its comorbidities based on a combination of imaging techniques with ultrasound. RECENT FINDINGS Peri-ictal perfusion changes can differentiate ictal stroke mimics from acute ischemic stroke if focal areas of increased perfusion are depicted by computed tomography or MRI. Postictal perfusion patterns in patients with persisting neurological symptoms are frequently normal and do not reach enough diagnostic sensitivity to differentiate between stroke and its mimics. Noninvasive magnetic resonance-techniques as arterial spin labeling may provide a higher sensitivity, especially in combination with diffusion-weighted and susceptibility-weighted MRI. Imaging guided focused ultrasound (FUS) bears the potential to ablate epileptogenic tissue and allows suppression of epileptic activity. Imaging guided blood-brain-barrier opening with FUS offers new options for local drug administration. SUMMARY MRI should be considered the method of choice in the differential diagnosis of peri-ictal imaging findings and their differential diagnosis. A combination of various MRI techniques with FUS opens new avenues for treatment of epilepsy.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.

The first human applications of ultrasound in medicine date back to 1939, when Reimar Pohlmann (Berlin, Germany) published data on therapy of neuralgia with ultrasound [...]

Humans generate recursive hierarchies in a variety of domains, including linguistic, social and visuo-spatial modalities. The ability to represent recursive structures has been hypothesized to increase the efficiency of hierarchical processing. Theoretical work together with recent empirical findings suggests that the ability to represent the self-similar structure of hierarchical recursive stimuli may be supported by internal neural representations that compress raw external information and increase efficiency. In order to explicitly test whether the representation of recursive hierarchies depends on internalized rules we compared the processing of visual hierarchies represented either as recursive or non-recursive, using task-free resting-state fMRI data. We aimed to evaluate the relationship between task-evoked functional networks induced by cognitive representations with the corresponding resting-state architecture. We observed increased connectivity within Default Mode Network (DMN) related brain areas during the representation of recursion, while non-recursive representations yielded increased connectivity within the Fronto-Parietal Control-Network. Our results suggest that human hierarchical information processing using recursion is supported by the DMN. In particular, the representation of recursion seems to constitute an internally-biased mode of information-processing that is mediated by both the core and dorsal-medial subsystems of the DMN. Compressed internal rule representations mediated by the DMN may help humans to represent and process hierarchical structures in complex environments by considerably reducing information processing load.

This study provides first data about the spatial variability of fMRI sensorimotor localizations when investigating the same subjects at different fMRI sites. Results are comparable to a previous patient study. We found a median between-site variability of about 6 mm independent of task (motor or sensory) and experimental standardization (high or low). An intraclass correlation coefficient analysis using data quality measures indicated a major influence of the fMRI site on variability. In accordance with this, within-site localization variability was considerably lower (about 3 mm). We conclude that the fMRI site is a considerable confound for localization of brain activity. However, when performed by experienced clinical fMRI experts, brain pathology does not seem to have a relevant impact on the reliability of fMRI localizations. Hum Brain Mapp 37:2151-2160, 2016. © 2016 Wiley Periodicals, Inc.

In Parkinson’s disease (PD) the prevalence of apraxia increases with disease severity implying that patients in early stages may already have subclinical deficits. The aim of this exploratory fMRI study was to investigate if subclinical aberrations of the praxis network are already present in patients with early PD. In previous functional imaging literature only data on basal motor functions in PD exists. Thirteen patients with mild parkinsonian symptoms and without clinically diagnosed apraxia and 14 healthy controls entered this study. During fMRI participants performed a pantomime task in which they imitated the use of visually presented objects. Patients were measured ON and OFF dopaminergic therapy to evaluate a potential medication effect on praxis abilities and related brain functions. Although none of the patients was apraxic according to De Renzi ideomotor scores (range 62–72), patients OFF showed significantly lower praxis scores than controls. Patients exhibited significant hyperactivation in left fronto-parietal core areas of the praxis network. Frontal activations were clearly dominant in patients and were correlated with lower individual praxis scores. We conclude that early PD patients already show characteristic signs of praxis network dysfunctions and rely on specific hyperactivations to avoid clinically evident apraxic symptoms. Subclinical apraxic deficits were shown to correlate with an activation shift from left parietal to left frontal areas implying a prospective individual imaging marker for incipient apraxia.

Brain activations in early-blind subjects during Braille reading indicate considerable cross-modal neuroplasticity in posterior brain areas. Up to now it is, however, not clear how far such neuroplastic reorganization processes reach and whether a specific brain activation pattern corresponds to a specific component of the Braille reading task. Therefore, this fMRI study investigates whether different cortical areas are functionally specialized for different aspects of Braille reading. The comprehensive Braille reading task was contrasted to three control tasks representing subcomponents of Braille reading (passive tactile stimulation, active tactile pattern recognition, Braille imagery). Results in 14 early-blind subjects indicate that only occipital and basal temporo-occipital brain areas show specific fMRI correlates for Braille reading. Central rolandic brain activations correlated with basic somatosensory processing and superior temporal activations were associated with higher level stimulus-independent language processing. In these latter areas no indications for neuroplastic reorganizations specific for Braille reading were found, despite strong activations during the Braille reading task.

Brain diseases are one of the most important problems in our rapidly ageing society. Currently, there are not many effective medications and surgical options are limited due to invasiveness and non‐invasive brain stimulation techniques cannot be well targeted and cannot access deep brain areas. A novel therapy is transcranial ultrasound which allows a variety of treatments without opening of the skull. Recent technological developments generated three revolutionary options including 1) targeted non‐invasive surgery, 2) highly targeted drug, antibody, or gene therapy via local opening of the blood–brain barrier, and 3) highly targeted brain stimulation to improve pathological brain functions. This progress report summarizes the current state of the art for clinical application and the results of recent patient investigations., Novel ultrasound techniques allow revolutionary new brain therapies. With pulsed ultrasound, highly targeted therapeutic brain stimulation to improve pathological brain functions is now possible. Higher energies allow targeted non‐invasive surgery and local opening of the blood–brain barrier for highly targeted drug, antibody, or gene therapy.

In article number https://doi.org/10.1002/advs.201902583, Roland Beisteiner and co‐workers describe a brain activation technique for treatment of Alzheimer's disease. Transcranial pulse stimulation (TPS) applies ultrashort ultrasound pulses to activate neuronal resources. A therapeutic breakthrough is secure clinical targeting and access to deep brain areas. After 2 weeks of treatment, memory performance improves for up to 3 months.

Ultrasound‐based brain stimulation techniques may become a powerful new technique to modulate the human brain in a focal and targeted manner. However, for clinical brain stimulation no certified systems exist and the current techniques have to be further developed. Here, a clinical sonication technique is introduced, based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS) which markedly differs from existing focused ultrasound techniques. In addition, a first clinical study using ultrasound brain stimulation and first observations of long term effects are presented. Comprehensive feasibility, safety, and efficacy data are provided. They consist of simulation data, laboratory measurements with rat and human skulls and brains, in vivo modulations of somatosensory evoked potentials (SEP) in healthy subjects (sham controlled) and clinical pilot data in 35 patients with Alzheimer's disease acquired in a multicenter setting (including neuropsychological scores and functional magnetic resonance imaging (fMRI)). Preclinical results show large safety margins and dose dependent neuromodulation. Patient investigations reveal high treatment tolerability and no major side effects. Neuropsychological scores improve significantly after TPS treatment and improvement lasts up to three months and correlates with an upregulation of the memory network (fMRI data). The results encourage broad neuroscientific application and translation of the method to clinical therapy and randomized sham‐controlled clinical studies., A new clinical brain stimulation technique is introduced, based on single ultrashort ultrasound pulses (transcranial pulse stimulation, TPS). Comprehensive feasibility, safety, and efficacy data for this new therapy are provided. Two weeks TPS treatment of 35 Alzheimer's patients reveals high treatment tolerability, no major side effects, and improved memory performance lasting up to three months.

a b s t r a c t Background: Cardiac arrest (CA) survivors experience cognitive deficits including post-traumatic stress disorder (PTSD). It is unclear whether these are related to cognitive/mental experiences and awareness during CPR. Despite anecdotal reports the broad range of cognitive/mental experiences and awareness associated with CPR has not been systematically studied. Methods: The incidence and validity of awareness together with the range, characteristics and themes relating to memories/cognitive processes during CA was investigated through a 4 year multi-center observational study using a three stage quantitative and qualitative interview system. The feasibility of objectively testing the accuracy of claims of visual and auditory awareness was examined using spe- cific tests. The outcome measures were (1) awareness/memories during CA and (2) objective verification of claims of awareness using specific tests. Results: Among 2060 CA events, 140 survivors completed stage 1 interviews, while 101 of 140 patients completed stage 2 interviews. 46% had memories with 7 major cognitive themes: fear; animals/plants; bright light; violence/persecution; deja-vu; family; recalling events post-CA and 9% had NDEs, while 2% described awareness with explicit recall of 'seeing' and 'hearing' actual events related to their resusci- tation. One had a verifiable period of conscious awareness during which time cerebral function was not expected.

Background Based on recent findings and our own impressions we took a closer look at the relationship between (inter)ictal photophobia and psychometric variables in migraine patients with photophobia. Findings For this study we included 29 (27 female) migraine patients and 31 (18 female) controls with a mean age of 31.6 ± 12.5 years and 24.0 ± 4.1 years, respectively. All participants filled out the Depression Anxiety Stress Scale (DASS). Interictal photophobia in patients was significantly higher than photophobia in controls (p = .001). Patients showed statistically significantly higher levels of depressive symptoms (p

Apraxia is a deficit in central motor planning impairing praxis functions such as gesture production or tool use that affects a substantial number of patients with advanced Parkinson's disease. We investigated the functional connectivity of the praxis network in patients in early stages of Parkinson's disease having an increased risk for apraxia and evaluated the influence of dopaminergic therapy on praxis abilities and related networks. 13 patients with mild to moderate Parkinson's disease (ON and OFF dopaminergic therapy) and 13 healthy controls completed a praxis sensitive functional MRI task and apraxia assessments. Functional connectivity analyses included a graph theoretical approach analyzing the global efficiency within the praxis network followed by a seed-to-voxel functional connectivity analysis. Patients in the OFF but not in the ON state showed significantly lower praxis scores than controls. Patients in both states displayed higher global efficiency within the praxis network than controls revealing the bilateral supramarginal gyri as hubs. Seed-to-voxel functional connectivity analyses showed aberrations of right-hemispheric praxis areas in the OFF but not in the ON state. Patients in the ON state exhibited a significantly higher functional connectivity between the supramarginal gyrus and the primary motor cortex, basal ganglia, and frontal areas than in the OFF state. Dopaminergic therapy seems to normalize praxis abilities and related praxis networks in early stages of Parkinson's disease potentially by facilitating the propagation of long-term representations of object-related actions to motor execution areas., Highlights • PD patients OFF dopaminergic therapy scored lower in apraxia tests than controls. • PD patients showed higher global efficiency in the praxis network than controls. • The praxis network expanded to the right hemisphere in patients OFF therapy. • Patients ON therapy showed higher connectivity between praxis and motor areas. • Dopaminergic therapy normalizes praxis abilities and related network connectivity.

To investigate intersite variability of clinical functional magnetic resonance (MR) imaging, including influence of task standardization on variability and use of various parameters to inform the clinician whether the reliability of a given functional localization is high or low.Local ethics committees approved the study; all participants gave written informed consent. Eight women and seven men (mean age, 40 years) were prospectively investigated at three experienced functional MR sites with 1.5- (two sites) or 3-T (one site) MR. Nonstandardized motor and highly standardized somatosensory versions of a frequently requested clinical task (localization of the primary sensorimotor cortex) were used. Perirolandic functional MR variability was assessed (peak activation variability, center of mass [COM] variability, intraclass correlation values, overlap ratio [OR], activation size ratio). Data quality measures for functional MR images included percentage signal change (PSC), contrast-to-noise ratio (CNR), and head motion parameters. Data were analyzed with analysis of variance and a correlation analysis.Localization of perirolandic functional MR activity differed by 8 mm (peak activity) and 6 mm (COM activity) among sites. Peak activation varied up to 16.5 mm (COM range, 0.4-16.5 mm) and 45.5 mm (peak activity range, 1.8-45.5 mm). Signal strength (PSC, CNR) was significantly lower for the somatosensory task (mean PSC, 1.0% ± 0.5 [standard deviation]; mean CNR, 1.2 ± 0.4) than for the motor task (mean PSC, 2.4% ± 0.8; mean CNR, 2.9 ± 0.9) (P.001, both). Intersite variability was larger with low signal strength (negative correlations between signal strength and peak activation variability) even if the task was highly standardized (mean OR, 22.0% ± 18.9 [somatosensory task] and 50.1% ± 18.8 [motor task]).Clinical practice and clinical functional MR biomarker studies should consider that the center of task-specific brain activation may vary up to 16.5 mm, with the investigating site, and should maximize functional MR signal strength and evaluate reliability of local results with PSC and CNR.

Presurgical planning with fMRI benefits from increased reliability and the possibility to reduce measurement time introduced by using ultra-high field. Echo-planar imaging suffers, however, from geometric distortions which scale with field strength and potentially give rise to clinically significant displacement of functional activation. We evaluate the effectiveness of a dynamic distortion correction (DDC) method based on unmodified single-echo EPI in the context of simulated presurgical planning fMRI at 7T and compare it with static distortion correction (SDC). The extent of distortion in EPI and activation shifts are investigated in a group of eleven patients with a range of neuropathologies who performed a motor task. The consequences of neglecting to correct images for susceptibility-induced distortions are assessed in a clinical context. It was possible to generate time series of EPI-based field maps which were free of artifacts in the eloquent brain areas relevant to presurgical fMRI, despite the presence of signal dropouts caused by pathologies and post-operative sites. Distortions of up to 5.1mm were observed in the primary motor cortex in raw EPI. These were accurately corrected with DDC and slightly less accurately with SDC. The dynamic nature of distortions in UHF clinical fMRI was demonstrated via investigation of temporal variation in voxel shift maps, confirming the potential inadequacy of SDC based on a single reference field map, particularly in the vicinity of pathologies or in the presence of motion. In two patients, the distortion correction was potentially clinically significant in that it might have affected the localization or interpretation of activation and could thereby have influenced the treatment plan. Distortion correction is shown to be effective and clinically relevant in presurgical planning at 7T.

Ultra-high-field magnetic resonance (UHF MR) systems (7 Tesla [7 T] and higher field strength) are expected to yield a twofold-to-threefold improvement in image signal-to-noise ratio (SNR) over 3 Tesla (3 T) MR scanners. Advances in multichannel radiofrequency (RF) technology provide an additional twofold-to-sixfold improvement in SNR over single-channel RF coils (Wiggins et al., 2005). Many fields require new methods to deal with increased B0 and B1 inhomogeneity, however, and sequences need to be modified to adapt to modified relaxation times of 1H and X nuclei at 7 T. In the following sections, we review the state of the art of 7 T methods and nascent applications in neuroimaging, musculoskeletal (MSK) imaging, studies of metabolism, and oncology.

BACKGROUND AND PURPOSE Impaired dexterity (fine hand movements) is often present in Parkinson's disease (PD), even at early to moderate disease stages. It has a detrimental impact on activities of daily living (ADL) such as buttoning, contributing to reduced quality of life. Limb-kinetic apraxia, a loss of the ability to make precise, independent but coordinated finger and hand movements, may contribute to impaired dexterity even more than bradykinesia per se. However, the impact of limb-kinetic apraxia on ADL remains controversial. Our aim was to identify the strongest predictor of buttoning and unbuttoning in PD. It was hypothesized that coin rotation (a surrogate of limb-kinetic apraxia) represents the most important determinant. METHODS Sixty-four right-handed, early to moderate PD patients were recruited from three movement disorder centers (Hoehn andYahr stages 1-3). Buttoning, unbuttoning and coin rotation (right and left hand) represented the target tasks. Motor impairment was assessed according to the Unified Parkinson's Disease Rating Scale. RESULTS Multiple linear regression analysis showed that coin rotation with the right hand was the only significant predictor of buttoning (P < 0.001) and unbuttoning (P = 0.002). Notably, measures of bradykinesia or overall motor impairment did not represent significant predictors. CONCLUSIONS Constituting the novel key finding, limb-kinetic apraxia seems to be particularly relevant for ADL requiring dexterity skills in PD, even at early to moderate disease stages. Our results prompt research into the pathophysiological background and therapeutic options to treat limb-kinetic apraxia. The simple coin rotation test provides valuable information about ADL-related dexterity skills.

Neural activity preceding force-loaded voluntary finger movement (the Bereitschaftsfeld) was recorded using 143-channel whole-scalp magnetoencephalography (MEG) in order to determine how the level of force produced during voluntary finger movement is represented in activity over different premovement time intervals localized to different cortical areas. Eighteen healthy subjects performed voluntary right index-finger extension movements against an inertial load of either 0, 100, or 200 g. Results showed that the earliest component of premovement activity, beginning between 1.5 and 1.0 s prior to movement and localized to the central midline around the region of supplementary/cingulate motor areas, was not modulated by the level of force required for movement. However, later premovement activity, occurring between 500 and 200 ms prior to movement onset, was significantly greater for the highest force movements compared with both intermediate (p < 0.05) and no weight-load conditions (p < 0.01). This component was localized to primary sensorimotor cortical areas, with greater source strength on the left side contralateral to movement. Results indicate that, although early premovement activity of the supplementary/cingulate motor areas does not appear to encode movement force, later premovement activity of the primary motor cortex is significantly greater for movements made with more force, not only during movement execution but also up to 500 ms prior in readiness for intended movements of greater force.

Despite there being an increasing number of installations of ultra high field MR systems (> 3 T) in clinical environments, no functional patient investigations have yet examined possible benefits for functional diagnostics. Here we performed presurgical localization of the primary motor hand area on 3 T and 7 T Siemens scanners with identical investigational procedures and comparable system specific sequence optimizations. Results from 17 patients showed significantly higher functional sensitivity of the 7 T system measured via percent signal change, mean t-values, number of suprathreshold voxels and contrast to noise ratio. On the other hand, 7 T data suffered from a significant increase of artifacts (ghosting, head motion). We conclude that ultra high field systems provide a clinically relevant increase of functional sensitivity for patient investigations., Highlights ► Comparison of 3 T and 7 T fMRI in functional diagnostics. ► Differences in presurgical localization of the primary motor hand area were examined. ► Results from 17 patients showed higher functional sensitivity for 7 T measurements.

For quantitative somatosensory testing in the clinical environment a microprocessor controlled MR-compatible stimulation device was developed. A main feature of this device is the use of an inflatable cuff allowing the application of defined test pressures (0–1000 mbar) to the skin surface. The cuff is pressurized by a piezoelectric proportional valve with embedded closed loop controller. The distortion of the pressure pulses, introduced by the tube between valve and cuff (tube lengths of 2 and 6 m), was evaluated. Two kinds of stimulation patterns were implemented by the microprocessor: constant frequency stimulation (selectable between 1 and 20 Hz) and stimulation with stepwise changing frequencies according to a pseudorandom sequence. Imaging tests (n = 8, index finger) showed more robust responses in S1 (contralateral) and S2 (bilaterally) if evoked by the random sequence. Both, the technical tests and the imaging results, demonstrate that this new stimulation system is well suited to set a standard for somatosensory stimulation in individual longitudinal studies or multicenter comparisons.

During presurgical diagnostics clinical functional magnetic resonance imaging is increasingly being performed to improve the management of epilepsy and tumor patients. Rapid technical developments in fMRI technology continuously further new diagnostic applications. Safe clinical application requires a profound and critical handling of the various methodological problems inherent with this complex technique. This article reviews relevant problems and solutions for patient investigations up to the preparation of an individual clinical fMRI report.

Purpose: To create a population-specific symmetric phase model and to evaluate the susceptibility-weighted imaging (SWI) phase in terms of phase shift using different segmentation methods (manual and automatic) and phase shift symmetry, which is expected as a marker for lateralized Parkinson's disease (PD) symptoms. Materials and Methods: SWI and T1-weighted data from 25 PD patients and five healthy controls were acquired on a 3T MRI system. A population-specific, symmetric phase model was developed. Regions of interest (ROIs) were defined manually on the phase model, manually on each individual data set, and automatically using model-based segmentation (MBS). Manually- and MBS- defined ROIs were compared using kappa values, and left-right phase symmetry was evaluated using correlation analysis. Results: Independent of the analysis method, a phase increase from the anterior to the posterior putamen, and the average phase value relationship substantia nigra > globus pallidus > red nucleus was found. Phase symmetry analysis shows a difference between lateralized and symmetric PD. Conclusion: The symmetric phase model helps to analyze phase data with similar accuracy, but a greatly reduced tracing effort compared to individual tracing and also allows evaluating left-right phase symmetries.

BACKGROUND AND PURPOSE: Functional MR imaging (fMRI) is a promising but, in some aspects, still debated noninvasive tool for functional language mapping. We developed a clinical fMRI overt language design at the sentential level to optimize sensitivity for language-related areas of the brain. To evaluate applicability and sensitivity, we investigated a consecutive series of presurgical patients with epilepsy with minimal morphologic brain abnormalities. MATERIALS AND METHODS: Thirty right-handed patients with temporal lobe epilepsy (TLE) and a control group of 23 right-handed healthy subjects participated in the study. The language design included semantic and syntactic error-detection tasks and was constructed to represent the most relevant aspects of everyday language demands. It was applied during block-designed fMRI runs. We performed image preprocessing and statistical analysis with SPM5 at a group level, applying widely used statistical criteria. The study was approved by the local ethics committee, and all participants gave written informed consent. RESULTS: Given the strict statistical criteria, the sensitivity for inferior frontal and posterior temporal activations (comprising Broca and Wernicke regions) was improved relative to previous findings in the literature. For both language areas, we found 100% sensitivity in healthy subjects (Brodmann areas, BA22 and BA44) and 97% sensitivity in patients (when including BA47). Lateralization results demonstrated the capability to detect atypical language lateralizations in patients, which were more frequent in than those in healthy subjects. CONCLUSIONS: We developed a clinical language fMRI design that integrates various relevant aspects of everyday language demands and provides robust localization of core language areas.

Although unilateral lesion studies concerning the opercular part of primary motor cortex report clinically severe motor deficits (e.g. anarthria, masticatory paralysis), functional lateralization of this area has not yet been addressed in neuroimaging studies. Using BOLD-FMRI, this study provides the first quantitative evaluation of a possible cortical lateralization of symmetric chin movements (rhythmic contraction of masticatory muscles) in right-handed healthy subjects and presurgical patients suffering tumorous lesions in the opercular primary motor cortex. Data were analyzed according to "activation volume" and "activation intensity". At group level, results showed a strong left-hemispheric dominance for chin movements in the group of healthy subjects. In contrast, patients indicated dominance of the healthy hemisphere. Here, a clinically relevant dissociation was found between "activation volume" and "activation intensity": Although "activation volume" may be clearly lateralized to the healthy hemisphere, "activation intensity" may indicate residual functionally important tissue close to the pathological tissue. In these cases, consideration of BOLD-FMRI maps with the exclusive focus on "activation volume" may lead to erroneous presurgical conclusions. We conclude that comprehensive analyses of presurgical fMRI data may help to avoid sustained postoperative motor deficits and dysarthria in patients with lesions in the opercular part of primary motor cortex.

Purpose: To evaluate the impact of data quality on the localization of brain activation in functional magnetic resonance imaging (fMRI) and to explore whether the temporal contrast-to-noise-ratio (CNR) provides a quantitative parameter to estimate fMRI quality. Materials and Methods: We investigated two methods for defining the CNR by comparing them on a single-run, single session, as well as on a group-wise basis. The CNRs of healthy subjects and a group of patients with brain lesions were calculated using two different strategies: one based on a general linear model (GLM) analysis (CNR_SPM), and one that acts as an adaptive low-pass filter and assumes that the high-frequency components contain the temporal noise (GNR_SG). Runs with low CNR were identified as outliers using a common exclusion criterion (2 x standard deviation (SD)). Results: The results of the two CNR methods are highly correlated. Both between and within subjects and patients the CNR showed quite large variations, but the average CNR did not differ between a group of healthy subjects and a patient group. In total, seven of 213 runs (3.3% of all runs) had to be excluded when CNR_SG was used, and 14 of 213 (6.6%) runs had to be excluded when CNR_SPM was used. Conclusion: Calculating the CNR using an adaptive low-pass filter gives similar results to a GLM-based approach and could be advantageous for cases in which the hemodynamic response function (HRF) differs significantly from common assumptions. The CNR can be used to identify and exclude runs with suboptimal CNR, and to identify sessions with insufficient data quality. The CNR may serve as a quantitative and intuitive parameter to assess the performancejand quality of clinical fMRI investigations, including information on both functional performance (contrast) and data quality (noise caused by the system and physiology).

This study provides first data about the spatial variability of fMRI sensorimotor localizations when investigating the same subjects at different fMRI sites. Results are comparable to a previous patient study. We found a median between‐site variability of about 6 mm independent of task (motor or sensory) and experimental standardization (high or low). An intraclass correlation coefficient analysis using data quality measures indicated a major influence of the fMRI site on variability. In accordance with this, within‐site localization variability was considerably lower (about 3 mm). We conclude that the fMRI site is a considerable confound for localization of brain activity. However, when performed by experienced clinical fMRI experts, brain pathology does not seem to have a relevant impact on the reliability of fMRI localizations. Hum Brain Mapp 37:2151–2160, 2016. © 2016 Wiley Periodicals, Inc.

Purpose: To investigate the spatiotemporal evolution of cortical activation during the initiation of optokinetic nystagmus using magnetoencephalography. Background: Previous imaging studies of optokinetic nystagmus in humans using positron emission tomography and functional magnetic resonance imaging discovered activation of a large set of cortical and subcortical structures during steady-state optokinetic stimulation, but did not provide information on the temporal dynamics of the initial response. Imaging studies have shown that cortical areas responsible for vision in occipital and temporo-occipital areas are involved, i.e. cortical areas control optokinetic stimulation in humans. Magnetoencephalography provides measures that reflect neural ensemble activity in the millisecond time scale, allowing the identification of early cortical components of visuomotor integration. Design/Methods: We studied neuromagnetic cortical responses during the initiation of optokinetic nystagmus in 6 right-handed healthy subjects. Neuromagnetic activity was recorded with a whole-head magnetoencephalograph, consisting of 143 planar gradiometers. Results: The mean (±SD) latency between stimulus onset and initiation of optokinetic nystagmus was 177.7 ± 59 ms. Initiation of optokinetic nystagmus evoked an early component in the primary visual cortex starting at 40-90 ms prior to the onset of the slow phase of nystagmus. Almost simultaneously an overlapping second component occurred bilaterally in the temporo-occipital area (visual motion areas), pronounced in the right hemisphere, starting at 10-60 ms prior to the slow-phase onset. Both components showed long-duration activity lasting for up to 100 ms after slow-phase onset. Conclusions: Our findings suggest that the initiation of optokinetic nystagmus induces early cortical activation in the occipital cortex and almost simultaneously bilaterally in the temporo-occipital cortex. These cortical regions might represent essential areas for the monitoring of retinal slip.

Objectives: The validity of 3 Tesla motor functional magnetic resonance imaging (fMRI) in patients with gliomas involving the primary motor cortex was investigated by intraoperative navigated motor cortex stimulation (MCS). Methods: Twenty two patients (10 males, 12 females, mean age 39 years, range 10–65 years) underwent preoperative fMRI studies, performing motor tasks including hand, foot, and mouth movements. A recently developed high field clinical fMRI technique was used to generate pre-surgical maps of functional high risk areas defining a motor focus. Motor foci were tested for validity by intraoperative motor cortex stimulation (MCS) employing image fusion and neuronavigation. Clinical outcome was assessed using the Modified Rankin Scale. Results: FMRI motor foci were successfully detected in all patients preoperatively. In 17 of 22 patients (77.3%), a successful stimulation of the primary motor cortex was possible. All 17 correlated patients showed 100% agreement on MCS and fMRI motor focus within 10 mm. Technical problems during stimulation occurred in three patients (13.6%), no motor response was elicited in two (9.1%), and MCS induced seizures occurred in three (13.6%). Combined fMRI and MCS mapping results allowed large resections in 20 patients (91%) (gross total in nine (41%), subtotal in 11 (50%)) and biopsy in two patients (9%). Pathology revealed seven low grade and 15 high grade gliomas. Mild to moderate transient neurological deterioration occurred in six patients, and a severe hemiparesis in one. All patients recovered within 3 months (31.8% transient, 0% permanent morbidity). Conclusions: The validation of clinically optimised high magnetic field motor fMRI confirms high reliability as a preoperative and intraoperative adjunct in glioma patients selected for surgery within or adjacent to the motor cortex.

Recent publications analyzing the influence of spatial smoothing on fMRI brain activation results demonstrated that smoothing may artificially combine activations from adjacent though functionally and anatomically distinct brain regions and that activation from large draining vessels may be smoothed into neighboring neuronal tissue. To investigate whether functional localizations may be artificially shifted by the smoothing procedure we performed replicability measurements. Localization centers of motor hand activations achieved during different conditions (isolated hand movements and simultaneous hand and chin movements) were compared with respect to smoothing effects. The voxel with the highest probability to represent a true positive activation was localized with a non-smoothed and a standard 4 x 4 x 6 mm smoothed correlational data analysis technique. Results show an increase of motor center aberrations between measurements by about 100% due to data smoothing indicating a statistically significant decrease in localization replicability.

The existence or non-existence of fine-scale motor somatotopy of the hand is a fundamental problem with regard to the functioning of the human brain. In contrast to seldom contradicted early twentieth century descriptions of activation overlap, descriptions of finger motor somatotopy faced disagreement. Recent blood-flow-related brain mapping data achieved with functional magnetic resonance imaging (fMRI) argue in favour of fine-scale somatotopy. However, considerable discrepancies between blood oxygen-level-dependent fMRI activations and intracortically recorded neuronal activity have been reported and it is unclear whether the blood flow results truly reflect the neuronal situation. We have used recent advances in magnetoencephalography to detect signals deriving directly from neuronal tissue. Besides replication of the overlap aspect, we found statistically significant evidence for the existence of a somatotopic aspect of human hand motor representation when comparing the fifth and first finger motor dipoles along the superior-inferior axis. The average location of the fifth finger was found to be 2.31 mm superior to the first finger.

Final outcome after surgical repair of peripheral nerve transections varies. Here, we present the first longitudinal functional magnetic resonance imaging (fMRI) obserof cortical somatosensory reorganization patterns after surgery. A 43-year-old man presented with isolated complete transecof the right median nerve and underwent immediate epineural end-to-end coaptation. Applying standardized vibrotactile median nerve stimulation, 3 T brain activation maps were evaluated at 1, 7, 15 weeks and 1 year after surgery. Initially, the affected hemisphere showed no primary activation but increased frontoparietal activity. After 1 year, primary activation had recovered, and frontoparietal activity was decreased relative to the nonaffected hemisphere. Based on these longitudinal fMRI patterns, we propose a new marker for restoration of somatosensory function, which may not be provided by electrophysiological methods.

Hierarchical structures play a central role in many aspects of human cognition, prominently including both language and music. In this study we addressed hierarchy in the visual domain, using a novel paradigm based on fractal images. Fractals are self-similar patterns generated by repeating the same simple rule at multiple hierarchical levels. Our hypothesis was that the brain uses different resources for processing hierarchies depending on whether it applies a "fractal" or a "non-fractal" cognitive strategy. We analyzed the neural circuits activated by these complex hierarchical patterns in an event-related fMRI study of 40 healthy subjects. Brain activation was compared across three different tasks: a similarity task, and two hierarchical tasks in which subjects were asked to recognize the repetition of a rule operating transformations either within an existing hierarchical level, or generating new hierarchical levels. Similar hierarchical images were generated by both rules and target images were identical. We found that when processing visual hierarchies, engagement in both hierarchical tasks activated the visual dorsal stream (occipito-parietal cortex, intraparietal sulcus and dorsolateral prefrontal cortex). In addition, the level-generating task specifically activated circuits related to the integration of spatial and categorical information, and with the integration of items in contexts (posterior cingulate cortex, retrosplenial cortex, and medial, ventral and anterior regions of temporal cortex). These findings provide interesting new clues about the cognitive mechanisms involved in the generation of new hierarchical levels as required for fractals.

Although qualitative reports about somatotopic representation of fingers in the human motor cortex exist, up to now no study could provide clear statistical evidence. The goal of the present study was to reinvestigate finger motor somatotopy by means of a thorough investigation of standardized movements of the index and little finger of the right hand. Using high resolution fMRI at 3 Tesla, blood oxygenation level-dependent (BOLD) responses in a group of 26 subjects were repeatedly measured to achieve reliable statistical results. The center of mass of all activated voxels within the primary motor cortex was calculated for each finger and each run. Results of all runs were averaged to yield an individual index and little finger representation for each subject. The mean center of mass localizations for all subjects were then submitted to a paired t test. Results show a highly significant though small scale somatotopy of fingerspecific activation patterns in the order indicated by Penfields motor homunculus. In addition, considerable overlap of finger specific BOLD responses was found. Comparing various methods of analysis, the mean center of mass distance for the two fingers was 2--3 mm with overlapping voxels included and 4--5 mm with overlapping voxels excluded. Our data may be best understood in the context of the work of Schieber (1999) who recently described overlapping somatotopic gradients in lesion studies with humans.