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Mark Hallett

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YNICL Journal 2024 Journal Article

Response to the Letter Concerning the Publication: Neuroimaging in Functional Neurological Disorder: State of the Field and Research Agenda. Perez DL et al. Neuroimage Clin. 2021;30:102623

  • David L. Perez
  • Timothy R. Nicholson
  • Ali A. Asadi-Pooya
  • Matthew Butler
  • Alan J. Carson
  • Anthony S. David
  • Quinton Deeley
  • Ibai Diez

In their letter, Tuller and colleagues raise concerns regarding the following introductory phrase and the linked Stone et al (2010) reference: "this renewed interest parallels recognition that FND [functional neurological disorder] is the 2nd most common outpatient neurologic diagnosis."While we appreciate there is complexity to epidemiological considerations in FND, we do not agree with the concerns raised.We share our perspective on this matter with the following four points:

YNICL Journal 2022 Journal Article

Multimodal imaging of essential tremor and dystonic tremor

  • Patrick Bédard
  • Pattamon Panyakaew
  • Hyun-Joo Cho
  • Mark Hallett
  • Silvina G. Horovitz

Despite recent advances in tremor and dystonia classification, it remains difficult to discriminate essential tremor from dystonic tremor as they are similar in appearance and no biomarker exists. Further, tremor can appear in the same or a different body part than the dystonia. The aim of the current study was to better understand the differential pathophysiology of these tremors. We designed a cross-sectional case-control study and recruited 16 patients with essential tremor, 16 patients with dystonic tremor, and 17 age-matched healthy volunteers. We used multi-modal imaging combining resting-state functional MRI, diffusion tensor imaging, and magnetic resonance spectroscopy. We measured functional connectivity of resting-state fMRI to assess connectivity in the tremor network, fractional anisotropy and mean diffusivity with diffusion tensor imaging, and GABA+, Glutamate/Glutamine, Choline, and N-Acetylaspartate with spectroscopy (adjusted to Creatine). Our results showed reduced functional connectivity of resting-state fMRI between the cerebellum and dentate nucleus bilaterally for the essential tremor group, but not the dystonic tremor group, compared to healthy volunteers. There was higher fractional anisotropy in the middle cerebellar peduncle bilaterally for the dystonic tremor group compared to the essential tremor group as well as for essential tremor group compared to healthy volunteers. There was also higher fractional anisotropy in the red nucleus and corticospinal tract for essential tremor and dystonic tremor groups compared to healthy volunteers. We also showed reduced mean diffusivity in the cerebellum of both essential tremor and dystonic tremor groups compared to healthy volunteers. Finally, we found elevated GABA+/Cr in the cerebellum of the essential tremor and dystonic tremor groups compared to healthy volunteers, but no difference emerged between essential tremor and dystonic tremor groups. We did not find group differences in the other metabolites. Our results indicate cerebellar alterations in essential tremor and dystonic tremor patients compared to healthy volunteers, and further changes in the cerebellum network for the dystonic tremor patients. suggesting that the cerebellum is affected differently in both tremors.

YNICL Journal 2022 Journal Article

Neural correlates of working memory and compensation at different stages of cognitive impairment in Parkinson’s disease

  • Takaaki Hattori
  • Richard Reynolds
  • Edythe Wiggs
  • Silvina G. Horovitz
  • Codrin Lungu
  • Gang Chen
  • Eiji Yasuda
  • Mark Hallett

Working memory (WM) impairment is one of the most frequent cognitive deficits in Parkinson's disease (PD). However, it is not known how neural activity is altered and compensatory responses eventually fail during progression. We aimed to elucidate neural correlates of WM and compensatory mechanisms in PD. Eighteen cognitively normal PD patients (PD-CogNL), 16 with PD with mild cognitive impairment (PD-MCI), 11 with PD with dementia (PDD), and 17 healthy controls (HCs) were evaluated. Subjects performed an n-back task. Functional MRI data were analyzed by event-related analysis for correct responses. Brain activations were evaluated by comparing them to fixation cross or 0-back task, and correlated with n-back task performance. When compared to fixation cross, PD-CogNL patients had more activation in WM areas than HCs for both the 2- and 3-back tasks. PD-MCI and PDD patients had more activation in WM areas than HCs for the 0- and 1-back task. 2-back task performance was correlated with brain activations (vs. 0-back task) in the bilateral dorsolateral prefrontal cortex and frontal eye field (FEF) and left rostral prefrontal cortex, caudate nucleus, inferior/superior parietal lobule (IPL/SPL), and anterior insular cortex as well as anterior cingulate cortex. 3-back task performance was correlated with brain activations (vs. 0-back task) in the left FEF, right caudate nucleus, and bilateral IPL/SPL. Additional activations on top of the 0-back task, rather than fixation cross, are the neural correlates of WM. Our results suggest PD patients have two types of compensatory mechanisms: (1) Hyperactivation for different WM load tasks depending on their cognitive status. PD-CogNL have hyperactivation for moderate and heavy working memory load tasks while maintaining normal working memory performance. In contrast, PD-MCI and PDD have hyperactivation for control task and light working memory load task, leaving less neural resources to further activate for more demanding tasks and resulting in impaired working memory performance. (2) Bilateral recruitment of WM-related areas, in particular the DLPFC, FEF, IPL/SPL and caudate nucleus, to improve WM performance.

YNICL Journal 2021 Journal Article

In vivo assessment of neurodegeneration in Spinocerebellar Ataxia type 7

  • Jacob A. Parker
  • Shabbir H. Merchant
  • Sanaz Attaripour-Isfahani
  • Hyun Joo Cho
  • Patrick McGurrin
  • Brian P. Brooks
  • Albert R. La Spada
  • Mark Hallett

Spinocerebellar Ataxia type 7 (SCA7) is a neurodegenerative disease characterized by progressive cerebellar ataxia and retinal degeneration. Increasing loss of visual function complicates the use of clinical scales to track the progression of motor symptoms, hampering our ability to develop accurate biomarkers of disease progression, and thus test the efficacy of potential treatments. We aimed to identify imaging measures of neurodegeneration, which may more accurately reflect SCA7 severity and progression. While common structural MRI techniques have been previously used for this purpose, they can be biased by neurodegeneration-driven increases in extracellular CSF-like water. In a cross-sectional study, we analyzed diffusion tensor imaging (DTI) data collected from a cohort of 13 SCA7 patients and 14 healthy volunteers using: 1) a diffusion tensor-based image registration technique, and 2) a dual-compartment DTI model to control for the potential increase in extracellular CSF-like water. These methodologies allowed us to assess both volumetric and microstructural abnormalities in both white and gray matter brain-wide in SCA7 patients for the first time. To measure tissue volume, we performed diffusion tensor-based morphometry (DTBM) using the tensor-based registration. To assess tissue microstructure, we computed the parenchymal mean diffusivity (pMD) and parenchymal fractional anisotropy (pFA) using the dual compartment model. This model also enabled us to estimate the parenchymal volume fraction (pVF), a measure of parenchymal tissue volume within a given voxel. While DTBM and pVF revealed tissue loss primarily in the brainstem, cerebellum, thalamus, and major motor white matter tracts in patients (p 1), pMD and pFA detected microstructural abnormalities in virtually all tissues brain-wide (p 1). The Scale for the Assessment and Rating of Ataxia trended towards correlation with cerebellar pVF (r = -0.66, p = 0.104, FDR corrected) and global white matter pFA (r = -0.64, p = 0.104, FDR corrected). These results advance our understanding of neurodegeneration in living SCA7 patients by providing the first voxel-wise characterization of white matter volume loss and gray matter microstructural abnormalities. Moving forward, this comprehensive approach could be applied to characterize the full spatiotemporal pattern of neurodegeneration in SCA7, and potentially develop an accurate imaging biomarker of disease progression.

YNICL Journal 2021 Journal Article

Neuroimaging in Functional Neurological Disorder: State of the Field and Research Agenda

  • David L. Perez
  • Timothy R. Nicholson
  • Ali A. Asadi-Pooya
  • Indrit Bègue
  • Matthew Butler
  • Alan J. Carson
  • Anthony S. David
  • Quinton Deeley

Functional neurological disorder (FND) was of great interest to early clinical neuroscience leaders. During the 20th century, neurology and psychiatry grew apart - leaving FND a borderland condition. Fortunately, a renaissance has occurred in the last two decades, fostered by increased recognition that FND is prevalent and diagnosed using "rule-in" examination signs. The parallel use of scientific tools to bridge brain structure - function relationships has helped refine an integrated biopsychosocial framework through which to conceptualize FND. In particular, a growing number of quality neuroimaging studies using a variety of methodologies have shed light on the emerging pathophysiology of FND. This renewed scientific interest has occurred in parallel with enhanced interdisciplinary collaborations, as illustrated by new care models combining psychological and physical therapies and the creation of a new multidisciplinary FND society supporting knowledge dissemination in the field. Within this context, this article summarizes the output of the first International FND Neuroimaging Workgroup meeting, held virtually, on June 17th, 2020 to appraise the state of neuroimaging research in the field and to catalyze large-scale collaborations. We first briefly summarize neural circuit models of FND, and then detail the research approaches used to date in FND within core content areas: cohort characterization; control group considerations; task-based functional neuroimaging; resting-state networks; structural neuroimaging; biomarkers of symptom severity and risk of illness; and predictors of treatment response and prognosis. Lastly, we outline a neuroimaging-focused research agenda to elucidate the pathophysiology of FND and aid the development of novel biologically and psychologically-informed treatments.

YNICL Journal 2018 Journal Article

Loss of inhibition in sensorimotor networks in focal hand dystonia

  • Cecile Gallea
  • Priyantha Herath
  • Valerie Voon
  • Alicja Lerner
  • John Ostuni
  • Ziad Saad
  • Shantalaxmi Thada
  • Jeffrey Solomon

OBJECTIVE: To investigate GABA-ergic receptor density and associated brain functional and grey matter changes in focal hand dystonia (FHD). METHODS: O. Anatomical images were also used to measure grey matter volume with voxel-based morphometry (VBM). RESULTS: In FHD patients compared to HV, the vermis VI of the right cerebellum and the left sensorimotor cortex had a decrease of Flumazenil binding potential (FMZ-BP), whereas the striatum and the lateral cerebellum did not show significant change. Bilateral inferior prefrontal cortex had increased FMZ-BP and an increase of perfusion, which correlated negatively with disease duration. Only the left sensorimotor cortex showed a decrease of grey matter volume. INTERPRETATION: Impairments of GABAergic neurotransmission in the cerebellum and the sensorimotor cortical areas could explain different aspects of loss of inhibitory control in FHD, the former being involved in maladaptive plasticity, the latter in surround inhibition. Reorganization of the inferior prefrontal cortices, part of the associative network, might be compensatory for the loss of inhibitory control in sensorimotor circuits. These findings suggest that cerebellar and cerebral GABAergic abnormalities could play a role in the functional imbalance of striato-cerebello-cortical loops in dystonia.

YNIMG Journal 2013 Journal Article

Cerebellum and integration of neural networks in dual-task processing

  • Tao Wu
  • Jun Liu
  • Mark Hallett
  • Zheng Zheng
  • Piu Chan

Performing two tasks simultaneously (dual-task) is common in human daily life. The neural correlates of dual-task processing remain unclear. In the current study, we used a dual motor and counting task with functional MRI (fMRI) to determine whether there are any areas additionally activated for dual-task performance. Moreover, we investigated the functional connectivity of these added activated areas, as well as the training effect on brain activity and connectivity. We found that the right cerebellar vermis, left lobule V of the cerebellar anterior lobe and precuneus are additionally activated for this type of dual-tasking. These cerebellar regions had functional connectivity with extensive motor- and cognitive-related regions. Dual-task training induced less activation in several areas, but increased the functional connectivity between these cerebellar regions and numbers of motor- and cognitive-related areas. Our findings demonstrate that some regions within the cerebellum can be additionally activated with dual-task performance. Their role in dual motor and cognitive task processes is likely to integrate motor and cognitive networks, and may be involved in adjusting these networks to be more efficient in order to perform dual-tasking properly. The connectivity of the precuneus differs from the cerebellar regions. A possible role of the precuneus in dual-tasks may be to monitor the operation of active brain networks.

YNIMG Journal 2012 Journal Article

Alteration of brain default network in subacute phase of injury in concussed individuals: Resting-state fMRI study

  • Brian Johnson
  • Kai Zhang
  • Michael Gay
  • Silvina Horovitz
  • Mark Hallett
  • Wayne Sebastianelli
  • Semyon Slobounov

There are a number of symptoms, both neurological and behavioral, associated with a single episode of r mild traumatic brain injury (mTBI). Neuropsychological testing and conventional neuroimaging techniques are not sufficiently sensitive to detect these changes, which adds to the complexity and difficulty in relating symptoms from mTBI to their underlying structural or functional deficits. With the inability of traditional brain imaging techniques to properly assess the severity of brain damage induced by mTBI, there is hope that more advanced neuroimaging applications will be more sensitive, as well as specific, in accurately assessing mTBI. In this study, we used resting state functional magnetic resonance imaging to evaluate the default mode network (DMN) in the subacute phase of mTBI. Fourteen concussed student-athletes who were asymptomatic based upon clinical symptoms resolution and clearance for aerobic exercise by medical professionals were scanned using resting state functional magnetic resonance imaging. Nine additional asymptomatic yet not medically cleared athletes were recruited to investigate the effect of a single episode of mTBI versus multiple mTBIs on the resting state DMN. In concussed individuals the resting state DMN showed a reduced number of connections and strength of connections in the posterior cingulate and lateral parietal cortices. An increased number of connections and strength of connections was seen in the medial prefrontal cortex. Connections between the left dorso-lateral prefrontal cortex and left lateral parietal cortex showed a significant reduction in magnitude as the number of concussions increased. Regression analysis also indicated an overall loss of connectivity as the number of mTBI episodes increased. Our findings indicate that alterations in the brain resting state default mode network in the subacute phase of injury may be of use clinically in assessing the severity of mTBI and offering some insight into the pathophysiology of the disorder.

YNIMG Journal 2012 Journal Article

Individuated finger control in focal hand dystonia: An fMRI study

  • Ryan D. Moore
  • Cecile Gallea
  • Silvina G. Horovitz
  • Mark Hallett

Objectives To better understand deficient selective motor control in focal hand dystonia by determining changes in striatal activation and connectivity in patients performing individuated finger control. Methods Functional imaging with a 3-Tesla magnetic resonance scanner was performed on 18 patients and 17 controls during non-symptom producing tasks requiring right-handed individuated or coupled finger control. A global linear model and psychophysiologic interaction model compared individuated to coupled tasks for patients and controls separately, and the results were submitted to a group analysis. The sensorimotor (posterior) and associative (anterior) parts of the putamen were considered as seed regions for the connectivity analysis. Results Compared to controls, patients had significant differences in activations and connectivity during individuated compared to coupled tasks: (i) decreased activations in the bilateral postcentral gyri, right associative posterior parietal areas, right cerebellum and left posterior putamen, while activations in the left anterior putamen were not different; (ii) increased connectivity of the left posterior putamen with the left cerebellum and left sensorimotor cortex; and (iii) increased connectivity of the left anterior putamen with bilateral supplementary motor areas, the left premotor cortex, and left cerebellum. Interpretation Decreased activations in the sensorimotor putamen and cerebellum controlling the affected hand might underlie low levels of surround inhibition during individuated tasks. For identical motor performance in both groups, increased connectivity of sensorimotor and associative striato-cortical circuits in FHD suggests that both affected and unaffected territories of the striatum participate in compensatory processes.

YNIMG Journal 2012 Journal Article

Neural correlates of blink suppression and the buildup of a natural bodily urge

  • Brian D. Berman
  • Silvina G. Horovitz
  • Brent Morel
  • Mark Hallett

Neuroimaging studies have elucidated some of the underlying physiology of spontaneous and voluntary eye blinking; however, the neural networks involved in eye blink suppression remain poorly understood. Here we investigated blink suppression by analyzing fMRI data in a block design and event-related manner, and employed a novel hypothetical time-varying neural response model to detect brain activations associated with the buildup of urge. Blinks were found to activate visual cortices while our block design analysis revealed activations limited to the middle occipital gyri and deactivations in medial occipital, posterior cingulate and precuneus areas. Our model for urge, however, revealed a widespread network of activations including right greater than left insular cortex, right ventrolateral prefrontal cortex, middle cingulate cortex, and bilateral temporo-parietal cortices, primary and secondary face motor regions, and visual cortices. Subsequent inspection of BOLD time-series in an extensive ROI analysis showed that activity in the bilateral insular cortex, right ventrolateral prefrontal cortex, and bilateral STG and MTG showed strong correlations with our hypothetical model for urge suggesting these areas play a prominent role in the buildup of urge. The involvement of the insular cortex in particular, along with its function in interoceptive processing, helps support a key role for this structure in the buildup of urge during blink suppression. The right ventrolateral prefrontal cortex findings in conjunction with its known involvement in inhibitory control suggest a role for this structure in maintaining volitional suppression of an increasing sense of urge. The consistency of our urge model findings with prior studies investigating the suppression of blinking and other bodily urges, thoughts, and behaviors suggests that a similar investigative approach may have utility in fMRI studies of disorders associated with abnormal urge suppression such as Tourette syndrome and obsessive–compulsive disorder.

YNIMG Journal 2012 Journal Article

Self-modulation of primary motor cortex activity with motor and motor imagery tasks using real-time fMRI-based neurofeedback

  • Brian D. Berman
  • Silvina G. Horovitz
  • Gaurav Venkataraman
  • Mark Hallett

Advances in fMRI data acquisition and processing have made it possible to analyze brain activity as rapidly as the images are acquired allowing this information to be fed back to subjects in the scanner. The ability of subjects to learn to volitionally control localized brain activity within motor cortex using such real-time fMRI-based neurofeedback (NF) is actively being investigated as it may have clinical implications for motor rehabilitation after central nervous system injury and brain–computer interfaces. We investigated the ability of fifteen healthy volunteers to use NF to modulate brain activity within the primary motor cortex (M1) during a finger tapping and tapping imagery task. The M1 hand area ROI (ROIm) was functionally localized during finger tapping and a visual representation of BOLD signal changes within the ROIm fed back to the subject in the scanner. Surface EMG was used to assess motor output during tapping and ensure no motor activity was present during motor imagery task. Subjects quickly learned to modulate brain activity within their ROIm during the finger-tapping task, which could be dissociated from the magnitude of the tapping, but did not show a significant increase within the ROIm during the hand motor imagery task at the group level despite strongly activating a network consistent with the performance of motor imagery. The inability of subjects to modulate M1 proper with motor imagery may reflect an inherent difficulty in activating synapses in this area, with or without NF, since such activation may lead to M1 neuronal output and obligatory muscle activity. Future real-time fMRI-based NF investigations involving motor cortex may benefit from focusing attention on cortical regions other than M1 for feedback training or alternative feedback strategies such as measures of functional connectivity within the motor system.

YNIMG Journal 2011 Journal Article

Effective connectivity of brain networks during self-initiated movement in Parkinson's disease

  • Tao Wu
  • Liang Wang
  • Mark Hallett
  • Yi Chen
  • Kuncheng Li
  • Piu Chan

Patients with Parkinson's disease (PD) have difficulty in performing self-initiated movements. The neural mechanism of this deficiency remains unclear. In the current study, we used functional MRI (fMRI) and psychophysiological interaction (PPI) methods to investigate the changes in effective connectivity of the brain networks during performance of self-initiated movement in PD patients. Effective connectivity is defined as the influence one neuronal system exerts over another. fMRIs were acquired in 18 PD patients and in 18 age- and sex-matched healthy controls, when performing a self-initiated right hand tapping task. We chose the left primary motor cortex (M1), rostral supplementary motor area (pre-SMA), left premotor cortex (PMC), left putamen, and right cerebellum as index areas for PPI analysis. During the performance of self-initiated movement, connectivity between the putamen and M1, PMC, SMA, and cerebellum was decreased in PD patients compared to controls. In contrast, connections between the M1, pre-SMA, PMC, parietal cortex, and cerebellum were increased in PD patients compared to controls. In addition, the M1, pre-SMA, PMC, and cerebellum also had less connectivity with the dorsal lateral prefrontal cortex in PD. In PD patients, the effective connectivity between the putamen and M1, PMC, SMA, and cerebellum negatively correlated with the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores; whereas the connectivity between the M1, pre-SMA, PMC, and cerebellum positively correlated with the UPDRS motor scores. Our findings demonstrate that the pattern of interactions of brain networks is disrupted in PD during performance of self-initiated movements. The striatum-cortical and striatum-cerebellar connections are weakened. In contrast, the connections between cortico-cerebellar motor regions are strengthened and may compensate for basal ganglia dysfunction. These altered interregional connections are more deviant when the disorder is more severe, and, therefore, our results give further insight into the explanation for the difficulty in performing self-initiated movements in PD.

YNIMG Journal 2011 Journal Article

Manual activity shapes structure and function in contralateral human motor hand area

  • Oliver Granert
  • Martin Peller
  • Christian Gaser
  • Sergiu Groppa
  • Mark Hallett
  • Arne Knutzen
  • Günther Deuschl
  • Kirsten E. Zeuner

From longitudinal voxel-based morphometry (VBM) studies we know that relatively short periods of training can increase regional grey matter volume in trained cortical areas. In 14 right-handed patients with writer's cramp, we employed VBM to test whether suppression (i. e. , immobilization) or enhancement (i. e. , training) of manual activity lead to opposing changes in grey matter in the contralateral primary motor hand area (M1HAND). We additionally used transcranial magnetic stimulation (TMS) to evaluate concurrent changes in regional excitability. Patients were recruited from a clinical trial which was designed to improve handwriting-associated dystonia. Initially the dystonic hand was immobilized for 4weeks with the intention to reverse faulty plasticity. After immobilization, patients accomplished a motor re-training for 8weeks. T1-weighted MRIs of the whole brain and single-pulse TMS measurements of the resting motor threshold (RMT) were performed every 4weeks. Immobilization of the right hand resulted in a relative grey matter decrease in the contralateral left M1HAND along with a decrease in corticomotor excitability as indexed by an increase in RMT. Subsequent training reversed the effects of immobilization, causing an increase in regional grey matter density and excitability of left M1HAND. The relative changes in grey matter correlated with the relative shifts in RMT. This prospective within-subject VBM study in task-specific hand dystonia shows that the grey matter density of M1HAND is dynamically shaped by the level of manual activity. This bi-directional structural plasticity is functionally relevant as local grey matter changes are mirrored by changes in regional excitability.

YNIMG Journal 2010 Journal Article

Effective connectivity of neural networks in automatic movements in Parkinson's disease

  • Tao Wu
  • Piu Chan
  • Mark Hallett

Patients with Parkinson's disease (PD) have difficulty in performing learned movements automatically. The neural mechanism of this deficiency remains unclear. In the current study, we used functional MRI (fMRI) and psychophysiological interaction (PPI) methods to investigate the changes in effective connectivity of the brain networks when movements become automatic in PD patients and age-matched normal controls. We found that during automaticity, the rostral supplementary motor area, cerebellum, and cingulate motor area had increased effective connectivity with brain networks in PD patients. In controls, in addition to these regions, the putamen also had automaticity-related strengthened interactions with brain networks. The dorsal lateral prefrontal cortex had more connectivity at the novel stage than in the automatic stage in normal subjects, but not in PD patients. The comparison of the PPI results between the groups showed that the rostral supplementary motor area, cerebellum, and cingulate motor area had significantly more increased effective connectivity with several regions in normal subjects than in PD. The changes of effective connectivity in some areas negatively correlated with the Unified Parkinson's Disease Rating Scale (UPDRS). Our findings show that some of the factors related to PD patients having difficulty achieving automaticity are less efficient neural coding of movement and failure to shift execution of automatic movements more subcortically. The changes of effective connectivity become more abnormal as the disorder progresses. In addition, in PD, the connections of the attentional networks are altered.

YNIMG Journal 2010 Journal Article

Gait disturbance associated with white matter changes: A gait analysis and blood flow study

  • Kazumi Iseki
  • Takashi Hanakawa
  • Kazuo Hashikawa
  • Hidekazu Tomimoto
  • Manabu Nankaku
  • Hiroshi Yamauchi
  • Mark Hallett
  • Hidenao Fukuyama

To clarify the mechanisms underlying gait disturbance secondary to age-related white matter changes (ARWMC), cerebral perfusion was investigated during treadmill walking. Twenty subjects with extensive hyperintensities in the periventricular and deep white matter on T2-weighted magnetic resonance images (MRI) were recruited. The ARWMC subjects were classified into gait-disturbed (GD) and non-GD groups according to clinical criteria. All the subjects underwent gait analyses and cerebral perfusion measurements during both gait and rest by using single photon emission computed tomography. The GD group showed greater double support time/phase and stride width, and slower walking velocity, than the non-GD group. In an analysis of pooled data from all the subjects, gait-induced increases in cerebral perfusion were observed in the supplementary motor areas (SMA), lateral premotor cortex (PMC), primary motor and somatosensory areas, visual areas, basal ganglia and cerebellum. A between-group comparison of gait-induced perfusion changes showed relative underactivation of the SMA, thalamus and basal ganglia, together with relative overactivation of the PMC, in the GD group compared with the non-GD group. In a separate correlation analysis including all the subjects, as the double support phase was longer (that was, gait disturbance was more severe), the gait-induced perfusion changes were proportionally reduced in the SMA, visual cortex, and thalamus. The present study suggests that abnormalities in the basal ganglia–thalamo–cortical loops partly explain gait disturbance observed in a subset of subjects with ARWMC.

YNIMG Journal 2008 Journal Article

High frequency rTMS modulation of the sensorimotor networks: Behavioral changes and fMRI correlates

  • Woo-Kyoung Yoo
  • Sung H. You
  • Myoung-Hwan Ko
  • Sung Tae Kim
  • Chang-hyun Park
  • Ji-Won Park
  • Suk Hoon Ohn
  • Mark Hallett

Repetitive transcranial magnetic stimulation (rTMS) to the primary motor cortex (M1) may induce functional modulation of motor performance and sensory perception. To address the underlying neurophysiological modulation following 10 Hz rTMS applied over M1, we examined cortical activation using 3T functional magnetic resonance imaging (fMRI), as well as the associated motor and sensory behavioral changes. The motor performance measure involved a sequential finger motor task that was also used as an activation task during fMRI. For sensory assessment, current perception threshold was measured before and after rTMS outside the MR scanner, and noxious mechanical stimulation was used as an activation task during fMRI. We found that significant activation in the bilateral basal ganglia, left superior frontal gyrus, bilateral pre-SMA, right medial temporal lobe, right inferior parietal lobe, and right cerebellar hemisphere correlated with enhanced motor performance in subjects that received real rTMS compared with sham-stimulated controls. Conversely, significant deactivation in the right superior and middle frontal gyri, bilateral postcentral and bilateral cingulate gyri, left SMA, right insula, right basal ganglia, and right cerebellar hemisphere were associated with an increase in the sensory threshold. Our findings reveal that rTMS induced rapid changes in the sensorimotor networks associated with sensory perception and motor performance and demonstrate the complexity of such intervention.

YNIMG Journal 2007 Journal Article

Imaging signal transduction via arachidonic acid in the human brain during visual stimulation, by means of positron emission tomography

  • Giuseppe Esposito
  • Giampiero Giovacchini
  • Margaret Der
  • Jeih-San Liow
  • Abesh K. Bhattacharjee
  • Kaizong Ma
  • Peter Herscovitch
  • Michael Channing

Background: Arachidonic acid (AA, 20: 4n-6), an important second messenger, is released from membrane phospholipid following receptor mediated activation of phospholipase A2 (PLA2). This signaling process can be imaged in brain as a regional brain AA incorporation coefficient K*. Hypothesis: K* will be increased in brain visual areas of subjects submitted to visual stimulation. Subjects and methods: Regional values of K* were measured with positron emission tomography (PET), following the intravenous injection of [1-11C]AA, in 16 healthy volunteers subjected to visual stimulation at flash frequencies 2. 9 Hz (8 subjects) or 7. 8 Hz (8 subjects), compared with the dark (0 Hz) condition. Regional cerebral blood flow (rCBF) was measured with intravenous [15O]water under comparable conditions. Results: During flash stimulation at 2. 9 Hz or 7. 8 Hz vs. 0 Hz, K* was increased significantly by 2. 3–8. 9% in Brodmann areas 17, 18 and 19, and in additional frontal, parietal and temporal cortical regions. rCBF was increased significantly by 3. 1–22%, often in comparable regions. Increments at 7. 8 Hz often exceeded those at 2. 9 Hz for both K* and rCBF. Decrements in both parameters also were produced, particularly in frontal brain regions. Conclusions: AA plays a role in signaling processes provoked by visual stimulation, since visual stimulation at flash frequencies of 2. 9 and 7. 8 Hz compared to 0 Hz modifies both K* for AA and rCBF in visual and related areas of the human brain. The two-stimulus condition paradigm of this study might be used with PET to image effects of other functional activations and of drugs on brain signaling via AA.

YNIMG Journal 2006 Journal Article

Neural correlates of counting of sequential sensory and motor events in the human brain

  • Kenji Kansaku
  • Ari Johnson
  • Marie-Laure Grillon
  • Gaëtan Garraux
  • Norihiro Sadato
  • Mark Hallett

Little is known about the ability to enumerate small numbers of successive stimuli and movements. It is possible that there exist neural substrates that are consistently recruited both to count sensory stimuli from different modalities and for counting movements executed by different effectors. Here, we identify a network of areas that was involved in enumerating small numbers of auditory, visual, and somatosensory stimuli, and in enumerating sequential movements of hands and feet, in the bilateral premotor cortex, presupplementary motor area, posterior temporal cortex, and thalamus. The most significant consistent activation across sensory and motor counting conditions was found in the lateral premotor cortex. Lateral premotor activation was not dependent on movement preparation, stimulus presentation timing, or number word verbalization. Movement counting, but not sensory counting, activated the anterior parietal cortex. This anterior parietal area may correspond to an area recruited for movement counting identified by recent single-neuron studies in monkeys. These results suggest that overlapping but not identical networks of areas are involved in counting sequences of sensory stimuli and sequences of movements in the human brain.

YNIMG Journal 2006 Journal Article

The role of the dorsal stream for gesture production

  • Esteban A. Fridman
  • Ilka Immisch
  • Takashi Hanakawa
  • Stephan Bohlhalter
  • Daniel Waldvogel
  • Kenji Kansaku
  • Lewis Wheaton
  • Tao Wu

Skilled gestures require the integrity of the neural networks involved in storage, retrieval, and execution of motor programs. Premotor cortex and/or parietal cortex lesions frequently produce deficits during performance of gestures, transitive more than intransitive. The dorsal stream links object information with object action, suggesting that mechanical knowledge of tool use is stored focally in the brain. Using event-related fMRI, we explored activity during instructed-delay transitive and intransitive hand gestures. The comparison between planning–preparation and execution of gestures demonstrated a temporal rostral to caudal gradient of activation in the ventral premotor cortex (PMv) and inferior to superior gradient of activation in the posterior parietal cortex (PPc). Comparison between transitive and intransitive gestures established a functional specificity within the dorsal stream for mechanical knowledge. Results demonstrate that not only PPc but also the PMv acts in the processing of sensorimotor information during gestures. This might be the substrate underlying selective deficits in ideomotor apraxia patients.

YNIMG Journal 2005 Journal Article

CASL fMRI of subcortico-cortical perfusion changes during memory-guided finger sequences

  • Gaëtan Garraux
  • Mark Hallett
  • S. Lalith Talagala

Arterial spin labeling (ASL) perfusion functional magnetic resonance imaging (fMRI) is an attractive alternative to BOLD fMRI. Nevertheless, current ASL fMRI techniques are limited by several factors that hamper more routine applications in humans. One of these factors is restricted brain coverage so that whole-brain ASL fMRI studies have never been reported. The present study tested the ability of a multislice continuous ASL (CASL) fMRI approach using a small surface coil placed on the subject's neck to map changes in regional cerebral blood flow (rCBF) throughout the brain while healthy individuals (N = 15) performed memory-guided sequential finger movements at a mean rate of ∼0. 5 Hz. As predicted by results from a large number of studies, reliable task-related increases in flow were detected across subjects not only in primary and associative cortical areas but also in subcortical brain regions. When normalized to baseline, rCBF increased 31% in the hand representation area (HRA) of left primary motor cortex (M1), 13% in the left supplementary motor area proper (SMA), 10% in the left dorsolateral prefrontal cortex (DLPFC), 10–18% in the bilateral intraparietal sulci, 6% in the HRA of left putamen, 10% in the left thalamus, and 17% in the right anterior cerebellum. In addition to these increases, 6% and 4% decreases in rCBF were detected in the HRA of the right M1 and the bilateral posterior cingulate sulci, respectively. These results demonstrate that perfusion-based fMRI using CASL with a separate labeling coil can now be used to characterize task-related flow changes in most of the brain volume with adequate accuracy and sensitivity.

YNIMG Journal 2004 Journal Article

A shared neural network for simple reaction time

  • Kenji Kansaku
  • Takashi Hanakawa
  • Tao Wu
  • Mark Hallett

Simple reaction time, a simple model of sensory-to-motor behavior, has been extensively investigated and its role in inferring elementary mental organization has been postulated. However, little is known about the neuronal mechanisms underlying it. To elucidate the neuronal substrates, functional magnetic resonance imaging (fMRI) signals were collected during a simple reaction task paradigm using simple cues consisting of different modalities and simple triggered movements executed by different effectors. We hypothesized that a specific neural network that characterizes simple reaction time would be activated irrespective of the input modalities and output effectors. Such a neural network was found in the right posterior superior temporal cortex, right premotor cortex, left ventral premotor cortex, cerebellar vermis, and medial frontal gyrus. The right posterior superior temporal cortex and right premotor cortex were also activated by different modality sensory cues in the absence of movements. The shared neural network may play a role in sensory triggered movements.

YNIMG Journal 2004 Journal Article

Regional cerebral blood flow correlates of the severity of writer's cramp symptoms

  • Alicja Lerner
  • Holly Shill
  • Takashi Hanakawa
  • Khalaf Bushara
  • Andrew Goldfine
  • Mark Hallett

Writer's cramp is a type of idiopathic focal dystonia with incompletely understood pathophysiology. Recent studies provide evidence that one element might be a sensory processing defect. We performed a PET study with O15 H2O to find out in which brain areas activity correlates with the severity of writer's cramp symptoms. Methods: We studied 10 patients with writer's cramp and 10 age- and gender-matched control subjects. There were seven conditions, each repeated twice: rest, writing, tapping with index finger for 2, 3, 4, and 5 min. For each scan, we obtained EMG recordings from the flexor digitorum superficialis (FDS), extensor indicis proprius (EIP) muscles, and a subjective score of severity of dystonia. Scans were realigned, normalized, smoothed, and analyzed using SPM99. Analysis included both intra- and intergroup comparisons and a correlation analysis where we used EMG recordings and subjective dystonia score as covariates. Results: Random effect analysis of the writing task showed overactivity of the primary sensory cortex and no significant underactivity. Correlation analysis of dystonia patients showed activation of SI when we used the subjective dystonia score as a covariate, and activation of both the SI and primary motor cortex when the normalized EMG score of FDS was used. Conclusion: While some overactivity of MI is not surprising, overactivity of SI is more dramatic and suggests a primary deficit in processing sensory feedback. Writer's cramp may arise in part as a dysfunction of sensory circuits, which causes defective sensorimotor integration resulting in co-contractions of muscles and overflow phenomena.

YNIMG Journal 2003 Journal Article

Power grip disinhibits the ipsilateral sensorimotor cortex: a TMS and fMRI study

  • Henrik Foltys
  • Ingo G Meister
  • Jürgen Weidemann
  • Roland Sparing
  • Armin Thron
  • Klaus Willmes
  • Rudolf Töpper
  • Mark Hallett

Electrophysiological studies have shown that forceful activation of the hand muscles (power grip) is accompanied by an increased excitability of the ipsilateral corticospinal system. This increase in excitability may be due to spinal or cortical mechanisms. Here we show with fMRI that this phenomenon is at least in part mediated at a cortical level. We used TMS to show that the increased ipsilateral excitability during a forceful maneuver leads to enhanced stimulus-response curves. fMRI was used to compare the activation during a repetitive hand movement with or without an accompanying power grip on the opposite site. The power grip reduced movement-related activation in the ipsilateral sensorimotor cortex. Peak deactivation was located in the left postcentral gyrus extending into the adjacent precentral gyrus. This finding suggests that a forceful activation of the hand muscles disinhibits a distinct functional representation in the ipsilateral sensorimotor cortex. Consequently, the excitability of the corticospinal system increases and less neuronal excitatory activity is needed to perform a given task. The results may be important for a variety of studies as they suggest that fMRI may show decreased hemodynamic response under conditions in which other neurophysiological methods have shown increased functional activity.

YNIMG Journal 2002 Journal Article

Generators of Movement-Related Cortical Potentials: fMRI-Constrained EEG Dipole Source Analysis

  • Keiichiro Toma
  • Takahiro Matsuoka
  • Ilka Immisch
  • Tatsuya Mima
  • Daniel Waldvogel
  • Benjamin Koshy
  • Takashi Hanakawa
  • Holly Shill

To clarify the precise location and timing of the motor cortical activation in voluntary movement, dipole source analysis integrating multiple constraints was conducted for the movement-related cortical potential (MRCP). Six healthy subjects performed single self-paced extensions of the right index finger at about 15-s intervals during EEG and event-related fMRI acquisitions. EEG was recorded from 58 scalp electrodes, and fMRI of the entire brain was obtained every 2. 6 s. Coordinates of the two methods were coregistered using anatomical landmarks. During dipole source modeling, a realistic three-layer head model was used as a volume conductor. To identify the number of uncorrelated sources in the MRCP, principal component (PC) analysis was performed, which was consistent with the existence of six sources in the left (Lt SM1) and right (Rt SM1) sensorimotor and medial frontocentral (MFC) areas. After dipoles were seeded at the activated spots revealed by fMRI, dipole orientations were fixed based on the interpretation of the topography of distribution of the PC. The strength of the six dipoles (three dipoles in Lt SM1, two in Rt SM1, and one in MFC) was then computed over time. Within the bilateral SM1, activation of the precentral gyrus occurs bilaterally with similar strength from −1. 2 s, followed by that of the precentral bank from −0. 5 s with contralateral preponderance. Subsequently, the postcentral bank becomes active only on the contralateral side at 0. 1 s after movement. Activation of the MFC shows timing similar to that of the bilateral precentral gyri. These deduced patterns of activation are consistent with previous studies of electrocorticography in humans.

YNIMG Journal 2001 Journal Article

The Role of the Medial Wall and Its Anatomical Variations for Bimanual Antiphase and In-Phase Movements

  • Ilka Immisch
  • Daniel Waldvogel
  • Peter van Gelderen
  • Mark Hallett

The medial wall of the frontal cortex is thought to play an important role for bimanual coordination. However, there is uncertainty regarding the exact neuroanatomical regions involved. We compared the activation patterns related to bimanual movements using functional magnetic resonance imaging in 12 healthy right-handed subjects, paying special attention to the anatomical variability of the frontal medial wall. The subjects performed unimanual right and left and bimanual antiphase and in-phase flexion and extension movements of the index finger. Activation of the right supplementary motor area (SMA) proper, right and left caudal cingulate motor area (CMA), and right and left premotor cortices was significantly stronger during bimanual antiphase than bimanual in-phase movements, indicating an important function of these areas with bimanual coordination. A frequent anatomical variation is the presence of the paracingulate sulcus (PCS), which might be an anatomical landmark to determine the location of activated areas. Seven subjects had a bilateral, three a unilateral right, and two a unilateral left PCS. Because the area around the PCS is functionally closer coupled to the CMA than to the SMA, activation found in the area around the PCS should be attributed to the CMA. With anatomical variations such as the presence of a PCS or a vertical branch of the cingulate sulcus, normalization and determination of the activation with the help of stereotaxic coordinates can cause an incorrect shift of CMA activation to the SMA. This might explain some of the discrepancies found in previous studies.

YNIMG Journal 2000 Journal Article

Gender Difference in Premotor Activity during Active Tactile Discrimination

  • Norihiro Sadato
  • Vicente Ibañez
  • Marie-Pierre Deiber
  • Mark Hallett

To investigate possible gender differences in tactile discrimination tasks, we measured cerebral blood flow of seven men and seven women using positron emission tomography and 15O water during tactile tasks performed with the right index finger. A nondiscrimination, somatosensory control task activated the left primary sensorimotor cortex and the left parietal operculum extending to the posterior insula without any gender difference. Compared with the control task, discrimination tasks activated the superior and inferior parietal lobules bilaterally, right dorsal premotor cortex, and dorsolateral prefrontal cortex in both genders, consistent with the notion of right hemisphere involvement during exploratory attentional movements. In both genders, symmetric activation of the superior and inferior parietal lobules and asymmetric activation of the right dorsolateral prefrontal cortex were confirmed. The former is consistent with the spatial representation of the tactile input and the latter with the spatial working memory. However, activation of the dorsal premotor cortex was asymmetric in men, whereas it was symmetric in women, the gender difference being statistically significant. This may suggest gender differences in motor programs for exploration in manipulospatial tasks such as tactile discrimination with active touch, possibly by greater interhemispheric interaction through the dorsal premotor cortices in women than in men.

YNIMG Journal 1998 Journal Article

Cerebral Processes Related to Visuomotor Imagery and Generation of Simple Finger Movements Studied with Positron Emission Tomography

  • Marie-Pierre Deiber
  • Vicente Ibañez
  • Manabu Honda
  • Norihiro Sadato
  • Ramesh Raman
  • Mark Hallett

Positron emission tomography was used to compare the functional anatomy of visual imagination and generation of movement. Subjects were asked to generate visual images of their finger movement in response to a preparatory signal. Four conditions were tested: in two, no actual movement was required; in the other two, a second signal prompted the subjects to execute the imagined movement. Which movement to imagine was either specified by the preparatory stimulus or freely selected by the subjects. Compared with a rest condition, tasks involving only imagination activated several cortical regions (inferoparietal cortex, presupplementary motor area, anterior cingulate cortex, premotor cortex, dorsolateral prefrontal cortex) contralateral to the imagined movement. Tasks involving both imagination and movement additionally increased activity in the ipsilateral cerebellum, thalamus, contralateral anteroparietal, and motor cortex and decreased activity in the inferior frontal cortex. These results support the hypothesis that distinct functional systems are involved in visuomotor imagination and generation of simple finger movements: associative parietofrontal areas are primarily related to visuomotor imagination, with inferior frontal cortex likely engaged in active motor suppression, and primary motor structures contribute mainly to movement execution.

YNIMG Journal 1996 Journal Article

Locating the Motor Cortex on the MRI with Transcranial Magnetic Stimulation and PET

  • Eric M. Wassermann
  • Binseng Wang
  • Thomas A. Zeffiro
  • Norihiro Sadato
  • Alvaro Pascual-Leone
  • Camilo Toro
  • Mark Hallett

Transcranial magnetic stimulation with a focal coil was used to map the cortical representation of a hand muscle in four healthy subjects. In each subject, the three-dimensional locations of the magnetic stimulation positions and about 400 positions on the surface of the head were digitized. The amplitude-weighted center of gravity of each subject's map was found, and a line perpendicular to the local head surface was projected inward. The digitized heads were registered with the subjects' MRIs using the scalp contours. The coordinate transformations yielded by this process were used to map the stimulation positions and the perpendicular line into the MRIs. Brain areas imaged with positron emission tomography (PET) and15O-labeled water, activated by movement of the same muscle, were registered with the MRIs using the brain contours. In all cases, the magnetic stimulation lines encountered the surface of the brain at the anterior lip of the central sulcus and ran along the precentral gyrus a few millimeters anterior to the central sulcus, coming within 5–22 mm of all the PET activation maxima. This technique demonstrates the accuracy of transcranial magnetic stimulation for locating the primary motor area.

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