Surround inhibition is a neural mechanism that assists in the focusing of excitatory drive to muscles responsible for a given movement (agonist muscles) by suppressing unwanted activity in muscles not relevant to the movement (surround muscles). The purpose of the study was to determine the contribution of GABAB receptor mediated intracortical inhibition as assessed by the cortical silent period (CSP) to the generation of surround inhibition in the motor system. Eight healthy adults (5 women and 3 men, 29.8 ± 9 years) performed isometric contractions with the abductor digiti minimi (ADM) muscle in separate conditions with and without an index finger flexion movement. The ADM motor evoked potential (MEP) amplitude and CSP duration elicited by transcranial magnetic stimulation (TMS) were compared between a control condition in which the ADM was activated independently and during conditions involving three phases (premotor, phasic, and tonic) of the index finger flexion movement. The MEP amplitude of the ADM was greater during the control condition compared with the phasic condition. Thus, the presence of surround inhibition was confirmed in the present study. Most critically, the CSP duration of the ADM decreased during the phasic stage of finger flexion compared to the control condition, which indicated a reduction of this type of intracortical inhibition during the phasic condition. These findings indicate that GABAB receptor mediated intracortical inhibition as measured by the duration of the CSP does not contribute to the generation of surround inhibition in hand muscles.
facilitation; transcranial magnetic stimulation; inhibition; motor cortex
Advanced neuroimaging techniques have shown promise in highlighting the subtle changes and nuances in mild traumatic brain injury (MTBI) even though clinical assessment has shown a return to pre-injury levels. Here we use 1H-magnetic resonance spectroscopy (1H-MRS) to evaluate the brain metabolites N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr) in the corpus callosum in MTBI. Specifically, we looked at the NAA/Cho, NAA/Cr, and Cho/Cr ratios in the genu and splenium. We recruited 20 normal volunteers (NV) and 28 student athletes recovering from the subacute phase of MTBI. The MTBI group was categorized based upon the number of MTBIs and time from injury to 1H-MRS evaluation. Significant reductions in NAA/Cho and NAA/Cr ratios were seen in the genu of the corpus callosum, but not in the splenium, for MTBI subjects, regardless of the number of MTBIs. MTBI subjects recovering from their first MTBI showed the greatest alteration in NAA/Cho and NAA/Cr ratios. Time since injury to 1H-MRS acquisition was based upon symptom resolution and did not turn out to be a significant factor. We observed that as the number of MTBIs increased, so did the length of time for symptom resolution. Unexpected findings from this study are that MTBI subjects showed a trend of increasing NAA/Cho and NAA/Cr ratios that coincided with increasing number of MTBIs.
concussion; 1H-MRS; MTBI; multiple MTBI
There is still considerable debate and controversy about whether EEG can be used as a robust clinical tool for assessment of mild traumatic brain injury (MTBI). Nonhomogeneous subject populations, inaccurate assessment of severity of brain injury, time since injury when EEG testing was performed, the lack of EEG research conducted serially and in conjunction with other behavioral measures as injury evolves over time may contribute to the existing controversies. In this study, we implemented a concussion assessment protocol combining a series of EEG and balance measures throughout one year post-injury to document the efficacy of EEG and balance measures as relate to differential recovery of patients suffering from MTBI.
Three hundred and eighty subjects at risk for MTBI were initially recruited for baseline testing. Forty nine from this initial subjects pool subsequently suffered a single episode of concussive blow and were tested on day 7, 15, 30 days, 6 months and 12 months post-injury. EEGs were recorded while sitting, standing on the force plate and then on a foam base of support with eyes open/closed conditions. EEG alpha power (8–12 Hz) and its percent suppression from sitting to standing postures were computed. The center of pressure (COP) measures were obtained from the force platform and analyzed for eyes open and eyes closed conditions.
Percent alpha power suppression from sitting to standing postural conditions significantly increased in MTBI subjects shortly after the injury (p < 0.01). Percent alpha power suppression significantly correlated with increased area of COP during standing posture with eye closed (r2 = 0.53, p < 0.01). The magnitude of alpha power suppression predicted the rate of recovery of this measure in sub-acute and chronic phases of injury (r2 = 0.609, p < 0.01). Finally, 85% of MTBI subjects who showed more than 20% of alpha power suppression in the acute phase of injury did not return to pre-injury status up to 12 months post-injury.
The efficacy of serially implemented EEG measures in conjunction with balance assessment over the course of MTBI evolution to document residual cerebral dysfunction was demonstrated. Specifically, alteration of EEG alpha power dynamics in conjunction with balance data in the acute phase of injury with respect to baseline measures may predict the rate of recovery from a single concussive blow.
Neurophysiological measures are excellent tools to assess the status and prognosis of patients with MTBI.
EEG; Mild traumatic brain injury; Balance; Center of pressure (COP) area
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.
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 interactions 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) putamen were considered as seed regions for the connectivity analysis.
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; (iii) increased connectivity of the left anterior putamen with bilateral supplementary motor areas, the left premotor cortex, and left cerebellum.
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.
motor control; focal hand dystonia; fMRI; striatum; putamen; cerebellum
The phenomenology of tremor is broad and its classification is complicated. Furthermore, the full range of tremor phenomenology with respect to specific neurological and neurodegenerative diseases has not been fully elaborated.
This right-handed man had a chief complaint of jaw tremor, which began approximately 20 years prior to death at age 101 years. He had been diagnosed with essential tremor (ET) by a local doctor. His examination at age 100 years was notable for marked jaw tremor at rest in the absence of other clear features of parkinsonism, mild kinetic tremor of the hands and, in the last year of life, a score of 22/41 on a cognitive screen. A senior movement disorder neurologist raised doubt about the “ET” diagnosis. The history and videotaped examination were reviewed by three additional senior tremor experts, who raised a number of diagnostic possibilities. A complete postmortem examination was performed by a senior neuropathologist, and was notable for the presence of tufted astrocytes, AT8-labeled glial cytoplasmic inclusions, and globose neuronal tangles. These changes were widespread and definitive. A neuropathological diagnosis of progressive supranuclear palsy was assigned.
This case presents with mixed and difficult to clinically classify tremor phenomenology and other neurological findings. The postmortem diagnosis was not predicted based on the clinical features, and it is possible that it does not account for all of the features. The case raises many interesting issues and provides a window into the complexity of the interpretation, nosology, and classification of tremor phenomenology.
Freezing of gait (FOG) is a commonly observed phenomenon in Parkinson’s disease, but its causes and mechanisms are not fully understood. This paper presents the development of a virtual reality (VR)-based body-weight supported treadmill interface (BWSTI) designed and applied to investigate FOG. The BWSTI provides a safe and controlled walking platform which allows investigators to assess gait impairments under various conditions that simulate real life. In order to be able to evoke FOG, our BWSTI employed a novel speed adaptation controller, which allows patients to drive the treadmill speed. Our interface responsively follows the subject’s intention of changing walking speed by the combined use of feedback and feedforward controllers. To provide realistic visual stimuli, a three dimensional VR system is interfaced with the speed adaptation controller and synchronously displays realistic visual cues. The VR-based BWSTI was tested with three patients with PD who are known to have FOG. Visual stimuli that might cause FOG were shown to them while the speed adaptation controller adjusted treadmill speed to follow the subjects’ intention. Two of the three subjects showed FOG during the treadmill walking.
BWSTI (body-weight supported treadmill interface); treadmill control; virtual reality; gait assessment; freeze of gait; Parkinson’s Disease
While writing performed by any body part is similar in style, indicating a common program, writing with the dominant hand is particularly skilled. We hypothesized that this skill utilizes a special motor network supplementing the motor equivalence areas. Using functional magnetic resonance imaging in 13 normal subjects, we studied nine conditions: writing, zigzagging and tapping, each with the right hand, left hand and right foot. We identified brain regions activated with the right (dominant) hand writing task, exceeding the activation common to right-hand use and the writing program, both identified without right-hand writing itself. Right-hand writing significantly differed from the other tasks. First, we observed stronger activations in the left dorsal prefrontal cortex, left intraparietal sulcus and right cerebellum. Second, the left anterior putamen was required to initiate all the tested tasks, but only showed sustained activation during the right-hand writing condition. Lastly, an exploratory analysis showed clusters in the left ventral premotor cortex and inferior and superior parietal cortices were only significantly active for right-hand writing. The increased activation with right-hand writing cannot be ascribed to increased effort, since this is a well-practiced task much easier to perform than some of the other tasks studied. Because parietal-premotor connections code for particular skills, it would seem that the parietal and premotor regions, together with basal ganglia-sustained activation likely underlie the special skill of handwriting with the dominant hand.
Recent work exploring the use of high-molecular weight alcohols to treat essential tremor (ET) has identified octanoic acid as a potential novel tremor-suppressing agent. We used an established harmaline-based mouse model of ET to compare tremor suppression by 1-octanol and octanoic acid. The dose-related effect on digitized motion power within the tremor bandwidth as a fraction of overall motion power was analyzed. Both 1-octanol and octanoic acid provided significant reductions in harmaline tremor. An 8-carbon alkyl alcohol and carboxylic acid each suppress tremor in a pre-clinical mouse model of ET. Further studies are warranted to determine the safety and efficacy of such agents in humans with ET.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0121-1) contains supplementary material, which is available to authorized users.
1-octanol; Octanoic acid; Essential tremor; Harmaline; Therapeutics
Dopaminergic medication-related Impulse Control Disorders (ICDs) such as pathological gambling and compulsive shopping have been reported in Parkinson disease (PD).
We hypothesized that dopamine agonists (DAs) would be associated with greater impulsive choice, or greater discounting of delayed rewards, in PD patients with ICDs (PDI).
Fourteen PDI patients, 14 PD controls without ICDs and 16 medication-free matched normal controls were tested on (i) the Experiential Discounting Task (EDT), a feedback-based intertemporal choice task, (ii) spatial working memory and (iii) attentional set shifting. The EDT was used to assess impulsivity choice (hyperbolic K-value), reaction time (RT) and decision conflict RT (the RT difference between high conflict and low conflict choices). PDI patients and PD controls were tested on and off DA.
On the EDT, there was a group by medication interaction effect [F(1,26)=5.62; p=0.03] with pairwise analyses demonstrating that DA status was associated with increased impulsive choice in PDI patients (p=0.02) but not in PD controls (p=0.37). PDI patients also had faster RT compared to PD controls F(1,26)=7.51 p=0.01]. DA status was associated with shorter RT [F(3,24)=8.39, p=0.001] and decision conflict RT [F(1,26)=6.16, p=0.02] in PDI patients but not in PD controls. There were no correlations between different measures of impulsivity. PDI patients on DA had greater spatial working memory impairments compared to PD controls on DA (t=2.13, df=26, p=0.04).
Greater impulsive choice, faster RT, faster decision conflict RT and executive dysfunction may contribute to ICDs in PD.
dopamine agonist; gambling; impulse control; Parkinson disease; delay discounting
Dystonia is typically considered a movement disorder characterized by motor manifestations, primarily involuntary muscle contractions causing twisting movements and abnormal postures. However, growing evidence indicates an important non-motor component to primary dystonia, including abnormalities in sensory and perceptual functions, as well as neuropsychiatric, cognitive and sleep domains. Here, we review this evidence and discuss its clinical and pathophysiological implications.
primary dystonia; non-motor; sensory; depression; endophenotypes; pathophysiology; quality of life
Dysfunction of the γ-aminobutyric acid-ergic system in Tourette syndrome may conceivably underlie the symptoms of motor disinhibition presenting as tics and psychiatric manifestations, such as attention deficit hyperactivity disorder and obsessive–compulsive disorder. The purpose of this study was to identify a possible dysfunction of the γ-aminobutyric acid-ergic system in Tourette patients, especially involving the basal ganglia-thalamo-cortical circuits and the cerebellum. We studied 11 patients with Tourette syndrome and 11 healthy controls. Positron emission tomography procedure: after injection of 20 mCi of [11C]flumazenil, dynamic emission images of the brain were acquired. Structural magnetic resonance imaging scans were obtained to provide an anatomical framework for the positron emission tomography data analysis. Images of binding potential were created using the two-step version of the simplified reference tissue model. The binding potential images then were spatially normalized, smoothed and compared between groups using statistical parametric mapping. We found decreased binding of GABAA receptors in Tourette patients bilaterally in the ventral striatum, globus pallidus, thalamus, amygdala and right insula. In addition, the GABAA receptor binding was increased in the bilateral substantia nigra, left periaqueductal grey, right posterior cingulate cortex and bilateral cerebellum. These results are consistent with the longstanding hypothesis that circuits involving the basal ganglia and thalamus are disinhibited in Tourette syndrome patients. In addition, the abnormalities in GABAA receptor binding in the insula and cerebellum appear particularly noteworthy based upon recent evidence implicating these structures in the generation of tics.
Tourette syndrome; tics; GABAA receptors; flumazenil; PET
We hypothesize that the evolution of mild traumatic brain injury (mTBI) may be related to differential effects of a concussive blow on the functional integrity of the brain default mode network (DMN) at rest and/or in response to physical stress. Accordingly, in this resting-state functional magnetic resonance imaging (fMRI) study, we examined 14 subjects 10±2 days post-sports-related mTBI and 15 age-matched normal volunteers (NVs) to investigate the possibility that the integrity of the DMN is disrupted at the resting state and/or following the physical stress test. First, all mTBI subjects were asymptomatic based upon clinical evaluation and neuropsychological (NP) assessments prior to the MRI session. Second, the functional integrity within the DMN, a main resting-state network, remained resilient to a single concussive blow. Specifically, the major regions of interest (ROIs) constituting the DMN (e.g., the posterior cingulate cortex [PCC]/precuneus area, the medial prefrontal cortex [MPFC], and left and right lateral parietal cortices [LLP and RLP]) and the connectivity within these four ROIs was similar between NVs and mTBI subjects prior to the YMCA physical stress test. However, the YMCA physical stress test disrupted the DMN, significantly reducing the magnitude of the connection between the PCC and left lateral parietal ROI, and PCC and right lateral parietal ROI, as well as between the PCC and MPFC in mTBI subjects. Thus while the DMN remained resilient to a single mTBI without exertion at 10 days post-injury, it was altered in response to limited physical stress. This may explain some clinical features of mTBI and provide some insight into its mechanism. This important finding should be considered by clinical practitioners when making decisions regarding return-to-play and clearing mTBI athletes for sports participation.
default mode network; resting state functional magnetic resonance imaging; subacute phase of mild traumatic brain injury
Artificial induction of plasticity by paired associative stimulation (PAS) in healthy subjects (HV) demonstrates Hebbian-like plasticity in selected inhibitory networks as well as excitatory ones. In a group of 17 patients with focal hand dystonia and a group of 19 HV, we evaluated how PAS and the learning of a simple motor task influence the circuits supporting long interval intracortical inhibition (LICI, reflecting activity of GABAB interneurons) and long latency afferent inhibition (LAI, reflecting activity of somatosensory inputs to the motor cortex).
In HV, PAS and motor learning induced LTP-like plasticity of excitatory networks and a lasting decrease of LAI and LICI in the motor representation of the targeted or trained muscle. The better the motor performance, the larger was the decrease of LAI. Although motor performance in the patient group was similar to that of the control group, LAI did not decrease during the motor learning as it did in the control group. In contrast, LICI was normally modulated. In patients the results after PAS did not match those obtained after motor learning: LAI was paradoxically increased and LICI did not exhibit any change.
In the normal situation, decreased excitability in inhibitory circuits after induction of LTP-like plasticity may help to shape the cortical maps according to the new sensorimotor task.
In patients, the abnormal or absent modulation of afferent and intracortical long-interval inhibition might indicate maladaptive plasticity that possibly contributes to the difficulty that they have to learn a new sensorimotor task.“
motor learning; dystonia; transcranial magnetic stimulation; GABA; plasticity
After clinical resolution of signs and symptoms of mild traumatic brain injury (MTBI) it is still not clear if there are residual abnormalities of structural or functional brain networks. We have previously documented disrupted interhemispheric functional connectivity in “asymptomatic” concussed individuals during the sub-acute phase of injury. Testing of 15 normal volunteers (NV) and 15 subacute MTBI subjects was performed within 24 hours of clinical symptoms resolution and medical clearance for the first stage of aerobic activity. In this MRS study we report (a) both in the genu and splenium of the corpus callosum NAA/Cho and NAA/Cr ratios were significantly (p<0.05) lower in MTBI subjects shortly after the injury compared to NVs, and (b) the metabolic ratio NAA/Cho in the splenium significantly correlated with the magnitude of inter-hippocampal functional connectivity in normal volunteers, but not in MTBI. This novel finding supports our hypothesis that the functional disruption of interhemispheric brain networks in MTBI subjects results from compromised metabolic integrity of the corpus callosum and that this persists despite apparent clinical return to baseline.
A major feature of focal hand dystonia (FHD) pathophysiology is the loss of inhibition. One inhibitory process, surround inhibition, for which the cortical mechanisms are still unknown, is abnormal in FHD. Since the ventral premotor cortex (PMv) plays a key role in the sensorimotor processing involved in shaping finger movements and has many projections onto the primary motor cortex (M1), we hypothesized that the PMv-M1 connections might play a role in surround inhibition. A paired-pulse transcranial magnetic stimulation (TMS) paradigm was used in order to evaluate and compare the PMv-M1 interactions during different phases (rest, preparation and execution) of an index finger movement in FHD patients and controls. A sub-threshold conditioning pulse (80% resting motor threshold) was applied to the PMv 6 ms before M1 stimulation. Right abductor pollicis brevis, a surround muscle, was the target muscle. In healthy controls, the results show that PMv stimulation induced an ipsilateral ventral premotor-motor inhibition at rest. This cortico-cortical interaction changed into an early facilitation (100 ms before movement onset) and turned back to inhibition 50 ms later. In FHD patients, this PMv-M1 interaction and its modulation were absent. Our results show that although the ipsilateral ventral premotor-motor inhibition does not play a key role in the genesis of surround inhibition, PMv has a dynamic influence on M1 excitability during the early steps of motor execution. The impaired cortico-cortical interactions observed in FHD patients might contribute, at least in part, to the abnormal motor command.
TMS; Motor Cortex; ventral premotor cortex; surround inhibition; movement disorders
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.
Real-time functional MRI; neurofeedback; finger tapping; motor imagery; primary motor cortex; electromyography
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, help 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.
Eye blinking; urge suppression; fMRI; electrooculography
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.
Default Mode Network; Resting State fMRI; Sub-acute mTBI
The capacity for subjects to learn to volitionally control localized brain activity using neurofeedback is actively being investigated. We aimed to investigate the ability of healthy volunteers to quickly learn to use visual feedback during real-time functional MRI (rtfMRI) to modulate brain activity within their anterior right insular cortex (RIC) localized during a blink suppression task, an approach of possible interest in the use of rtfMRI to reduce urges. The RIC region of interest (RIC-ROI) was functionally localized using a blink suppression task, and blood-oxygen level dependent (BOLD) signal changes within RIC-ROI used to create a constantly updating display fed back to the subject in the scanner. Subjects were instructed to use emotional imagery to try and increase activity within RIC-ROI during four feedback training runs (FB1–FB4). A “control” run (CNTRL) before training and a “transfer” run (XSFR) after training were performed without feedback to assess for baseline abilities and learning effects. Fourteen participants completed all neurofeedback training runs. At the group-level, increased BOLD activity was seen in the anterior RIC during all the FB runs, but a significant increase in the functionally defined RIC-ROI was only attained during FB2. In atlas-defined insular cortex ROIs, significant increases were seen bilaterally during the CNTRL, FB1, FB2, and FB4 runs. Increased activity within the insular cortices did not show lateralization. Training did, however, result in a significant increase in functional connectivity between the RIC-ROI and the medial frontal gyrus when comparing FB4 to FB1. Since neurofeedback training did not lead to an increase in BOLD signal across all feedback runs, we suggest that learning to control one’s brain activity in this fashion may require longer or repeated rtfMRI training sessions.
neural modulation; real-time fMRI; biofeedback; insular cortex; urges
Patients with Tourette Syndrome often state that their sensitivity to sensations is equally or more disruptive than are motor tics. However, their sensory sensitivity is not addressed by standard clinical assessments nor is it a focus of research. This lapse likely results from our limited awareness and understanding of the symptom. In this study we 1) defined the patients’ experience of sensitivity to external stimuli in detail, and 2) tested two hypotheses regarding its origin.
First, we administered a lengthy questionnaire and in-depth interviews to adult Tourette patients (n=19) and age-matched healthy volunteers (n=19). Eighty percent of patients described a heightened sensitivity to external stimuli, with examples among all 5 sensory modalities. Bothersome stimuli were characterized as faint, repetitive or constant, and non-salient, whereas intense stimuli were well-tolerated.
We then determined whether the sensitivity could be due to an increased ability to detect faint stimuli. After measuring the threshold of detection for olfactory and tactile stimuli among the patients and healthy volunteers, we found no significant difference for either sensory modality. These results indicate that patients’ perceived sensitivity derives from altered central processing rather than from enhanced peripheral detection.
Lastly, we assessed one aspect of processing: the perception of intensity. When subjects rated the intensity of near-threshold tactile and olfactory stimuli, there was a surprising difference: Tourette patients more frequently used the lowest range of the scale compared with healthy volunteers. Future research is necessary to define the anatomical and physiological basis of the patients’ experience of heightened sensitivity.
Tourette syndrome; tic; sensory; threshold
We investigated the effect of electrode area and inter-electrode distance on the spatial distribution of the current density in transcranial direct current stimulation (tDCS). For this purpose, we used the finite element method to compute the distribution of the current density in a four layered spherical head model using various electrode montages, corresponding to a range of electrode sizes and inter-electrode distances. We found that smaller electrodes required slightly less current to achieve a constant value of the current density at a reference point on the brain surface located directly under the electrode center. Under these conditions, smaller electrodes also produced a more focal current density distribution in the brain, i.e., the magnitude of the current density fell more rapidly with distance from the reference point. The combination of two electrodes with different areas produced an asymmetric current distribution that could lead to more effective and localized neural modulation under the smaller electrode than under the larger one. Focality improved rapidly with decreasing electrode size when the larger electrode sizes were considered but the improvement was less marked for the smaller electrode sizes. Also, focality was not affected significantly by inter-electrode distance unless two large electrodes were placed close together. Increasing the inter-electrode distance resulted in decreased shunting of the current through the scalp and the CSF, and decreasing electrode area resulted in increased current density on the scalp under the edges of the electrode.
Our calculations suggest that when working with conventional electrodes (25–35 cm2), one of the electrodes should be placed just “behind” the target relative to the other electrode, for maximum current density on the target. Also electrodes with areas in the range 3.5 to 12 cm2 may provide a better compromise between focality and current density in the scalp than the traditional electrodes. Finally, the use of multiple small return electrodes may be more efficient than the use of a single large return electrode.
tDCS; stimulation; electrode area; inter-electrode distance; focality; finite element method
Parkinsonism can be psychogenic, and psychogenic parkinsonism is about 10% of psychogenic movement disorder patients. Patients can present with any feature or combination of features of organic Parkinson’s disease. There are clinical clues that can lead to the correct diagnosis, and laboratory testing with clinical neurophysiology or DAT (dopamine transporter) scanning can be helpful as well. Patients may have both organic Parkinson’s disease and psychogenic parkinsonism, and this might be considered a psychologically induced aggravation of the organic disorder.
Parkinson’s disease; psychogenic movement disorder; conversion; tremor; Bradykinesia; rigidity; gait disorder; DAT scan
Existing therapeutic options for management of essential tremor are frequently limited by poor efficacy and adverse effects. Likely the most potent tremor suppressant used is ethanol, although its use is prohibitive due to a brief therapeutic window, and the obvious implications of excessive alcohol use. Longer-chain alcohols have been shown to suppress tremor in harmaline animal models, and appear to be safe and well tolerated in 2 prior studies in humans. Here we report on the findings of a phase I/II study of 1-octanol designed to explore pharmacokinetics, efficacy, and safety. The most significant finding was the identification of octanoic acid as the product of rapid 1-octanol metabolism. Furthermore, the temporal profile of efficacy closely matches the plasma concentration of octanoic acid. Therefore, these findings identify a novel class of compound (e.g., carboxylic acids) with tremor suppressive properties in ET. Administration of 1-octanol also appears to be safe based on various measures collected. Essential tremor (ET) is the most common tremor disorder, with tremors occurring during static posturing or movement. These tremors are known to briefly improve in many cases after alcohol (ethanol) consumption. Two previous studies of a longer chain alcohol, 1-octanol, have demonstrated longer duration tremor-suppressive effects without the occurrence of intoxication. The aim of this study was to characterize the pharmacokinetics of 1-octanol and its primary metabolite octanoic acid using two formulations, along with additional safety and efficacy measures. Participants with proven ethanol-responsive ET were recruited into 1 of 2 parts: (part A) a dose escalation study (1–64 mg/kg; n = 4), and (part B) a fixed dose (64 mg/kg; n = 10) balanced, open-label crossover design. Two participants in part B then completed an exploratory part C evaluating 128 mg/kg.Plasma samples were collected at 10 intervals during a 6-hour period postingestion. Efficacy was assessed using spirography, whereas safety was assessed with electrocardiograms, vital signs, adverse effects surveys, and an intoxication assessment. Plasma concentrations of 1-octanol were detectable at low levels whereas octanoic acid (OA) concentrations were approximately 100-fold higher. The half-life of OA was 87.6minutes. This was matched by a clinical reduction in tremor severity of 32% at 90 minutes, assessed using spirography. The safety profile was favorable, with the most commonly reported adverse effect being dysgeusia (38%). Early detection and higher plasma concentrations of OA are a product of rapid metabolism of 1-octanol.OA pharmacokinetics mirrored the timing of clinical improvement. These findings provide preliminary evidence for a new class of compound that may be effective in the treatment of ET.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-011-0045-1) contains supplementary material, which is available to authorized users.
1-Octanol; Octanoic acid; Essential tremor; Alcohol; Therapeutics; Spirography
Focal hand dystonia may be task-specific as is the case with writer’s cramp (WC). In early stages, the task-specificity can be so specific that it may be mistaken for a psychogenic movement disorder.
We describe four patients who showed extreme task specificity in WC. They initially only had problems writing either a single letter or number. Although they were largely thought to be psychogenic, they progressed to typical WC.
Early recognition of this condition may provide an opportunity for early initiation of treatment.
Dystonia; Movement Disorders; Clinical Neurology