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In the 1980s, following Newcombe's observations, Ungerleider and Mishkin put forward the functional subdivision of the visual system into a ventral stream dedicated to object perception and a dorsal stream dedicated to space perception. Ten years after this discovery, the perception-action model re-defined the dorsal stream as responsible for non-conscious visual guidance, and most recently a tripartition has been suggested to account for a variety of visuospatial functions. Here, we investigated the neural underpinnings of object and space perception by combining the administration of the Visual Object Space Perception (VOSP) battery with a voxel-based lesion symptom mapping (VLSM) approach in a large sample of patients with penetrating traumatic brain injury (pTBI). First, our results provided new support for the complementary role of both hemispheres in object recognition. The right lateral occipital complex was found to be critical in early perceptual discrimination, whereas more anterior temporal and frontal regions in the left hemisphere were found to be critical in more complex forms of object discrimination and recognition. Second, our findings confirmed that space perception depended on the integrity of the right inferior parietal lobule (IPL) and revealed that a network linking the right IPL with the right premotor cortex was critical for the perception of spatial relationships in both 2D and 3D representations. Taken together, our results supported the functional subdivision of the visual system and shed new light on the specific processes involved along both the dorsal and the ventral streams.

Summary Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes— MAPT , GRN , and C9orf72 —have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with FTD and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with FTD and 4308 controls), we did separate association analyses for each FTD subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and FTD overlapping with motor neuron disease [FTD-MND]), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p −8 ) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p −8 ). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, HLA locus (immune system), for rs9268877 (p=1·05 × 10 −8 ; odds ratio=1·204 [95% CI 1·11–1·30]), rs9268856 (p=5·51 × 10 −9 ; 0·809 [0·76–0·86]) and rs1980493 (p value=1·57 × 10 −8 , 0·775 [0·69–0·86]) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38 / CTSC (the transcripts of which are related to lysosomal biology), for the behavioural FTD subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10 −7 ; 0·814 [0·71–0·92]). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis . Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center.

Deficit in the ability to understand and predict the mental states of others is one of the central features of traumatic brain injury (TBI), leading to problems in social-daily life such as social withdrawal and the inability to maintain work or family relationships. Although several functional neuroimaging studies have identified a widely distributed brain network involved in the Reading the Mind in the Eyes Test (RMET), the necessary brain regions engaged in this capacity are still heavily debated. In this study, we combined the RMET with a whole-brain voxel-based lesion symptom mapping (VLSM) approach to identify brain regions necessary for adequate RMET performance in a large sample of patients with penetrating TBI (pTBI). Our results revealed that pTBI patients performed worse on the RMET compared to non-head injured controls, and impaired RMET performance was associated with lesions in the left inferior frontal gyrus (IFG). Our findings suggest that the left IFG is a key region in reading the mind in the eyes, probably involved in a more general impairment of a semantic working memory system that facilitates reasoning about what others are feeling and thinking as expressed by the eyes.

The prefrontal cortex is the single largest brain region in human beings. We proposed a technique to investigate the functional similarities and dissimilarities in the prefrontal area using the functional Near Infrared Spectroscopy (fNIRS) device.

Background: In an earlier study comparing obsessive-compulsive disorder (OCD) patients to psychiatrically screened normals, we found lowered motor evoked potential (MEP) threshold to transcranial magnetic stimulation (TMS) and decreased intracortical inhibition in OCD. We sought to determine whether this pattern was specific to OCD. Methods: We measured the threshold and amplitude of MEPs to single and paired (subthreshold-suprathreshold; 3, 4, 10, 15 msec intervals) TMS in 46 healthy volunteers (23 women, 23 men) who were given the NEO-PI-R personality inventory. Nineteen of the men also received cognitive and motor tests. Results: The paired-pulse conditioned/unconditioned MEP amplitude ratios correlated with Neuroticism (N), a stable measure of trait-level anxiety and other negative emotions, in the whole sample ( r = 0.48; p = 0.0006), and in the men ( r = 0.63; p = 0.0009). There were no other significant correlations. Conclusions: This relationship reflects a factor that contributes to both personality and cortical regulation. It was not statistically significant in women, probably because of confounding hormonal influences on excitability. Decreased intracortical inhibition may be related more to trait anxiety and depression, which are high in OCD, than to OCD itself. However, the MEP threshold (significantly lowered in OCD) was unrelated to N.

Transcranial magnetic stimulation (TMS) has been proposed as a means of improving or restoring cortical function in psychiatric and neurologic disorders. Movement disorders have attracted the attention of neurologists interested in the use of TMS as treatment. In Parkinson's disease, physiologic data and some clinical trials suggest that TMS may have a beneficial effect on movement. However, some of the laboratory data have been impossible to replicate, and the trials have lacked appropriate controls. In focal dystonia and tic disorder, TMS may suppress abnormal movements, but the data are preliminary. In the epileptic movement disorder cortical myoclonus, benefits have been elusive so far. TMS may have therapeutic potential in movement disorders, but further work is needed.

Background: High (10–20 Hz) and low frequency (1–5 Hz) repetitive transcranial magnetic stimulation (rTMS) have been explored for possible therapeutic effects in the treatment of neuropsychiatric disorders. As part of a double-blind, placebo-controlled, crossover study evaluating the antidepressant effect of daily rTMS over the left prefrontal cortex, we evaluated changes in absolute regional cerebral blood flow (rCBF) after treatment with 1- and 20-Hz rTMS. Based on preclinical data, we postulated that high frequency rTMS would increase and low frequency rTMS would decrease flow in frontal and related subcortical circuits. Methods: Ten medication-free, adult patients with major depression (eight unipolar and two bipolar) were serially imaged using 15 O water and positron emission tomography to measure rCBF. Each patient was scanned at baseline and 72 hours after 10 daily treatments with 20-Hz rTMS and 10 daily treatments with 1 Hz rTMS given in a randomized order. TMS was administered over the left prefrontal cortex at 100% of motor threshold (MT). Significant changes in rCBF from pretreatment baseline were determined by paired t test. Results: Twenty-hertz rTMS over the left prefrontal cortex was associated only with increases in rCBF. Significant increases in rCBF across the group of all 10 patients were located in the prefrontal cortex (L > R), the cingulate gyrus (L ≫ R), and the left amygdala, as well as bilateral insula, basal ganglia, uncus, hippocampus, parahippocampus, thalamus, and cerebellum. In contrast, 1-Hz rTMS was associated only with decreases in rCBF. Significant decreases in flow were noted in small areas of the right prefrontal cortex, left medial temporal cortex, left basal ganglia, and left amygdala. The changes in mood following the two rTMS frequencies were inversely related ( r = −.78, p n = 10) such that individuals who improved with one frequency worsened with the other. Conclusions: These data indicate that 2 weeks of daily 20-Hz rTMS over the left prefrontal cortex at 100% MT induce persistent increases in rCBF in bilateral frontal, limbic, and paralimbic regions implicated in depression, whereas 1-Hz rTMS produces more circumscribed decreases (including in the left amygdala). These data demonstrate frequency-dependent, opposite effects of high and low frequency rTMS on local and distant regional brain activity that may have important implications for clinical therapeutics in various neuropsychiatric disorders.

The aim of this study was to evaluate corticospinal excitability of both hemispheres during the reaction time (RT) using transcranial magnetic stimulation (TMS). Nine right-handed subjects performed right and left thumb extensions in simple (SRT), choice (CRT) and go/no-go auditory RT paradigms. TMS, inducing motor-evoked potentials (MEPs) simultaneously in the extensor pollicis brevis muscles bilaterally, was applied at different latencies from the tone. For all paradigms, MEP amplitudes on the side of movement increased progressively in the 80-120 ms before EMG onset, while the resting side showed inhibition. The inhibition was significantly more pronounced for right than for left thumb movements. For the left SRT, significant facilitation occurred on the right after EMG onset. Initial bilateral facilitation occurred in SRT trials with slow RT. After no-go tones, bilateral inhibition occurred at a time corresponding to the mean RT to go tones. The timing of the corticospinal rise in excitability on the side of movement was independent of task difficulty and RT. This suggests that corticospinal activation is, to some extent, in series and not in parallel with stimulus processing and response selection. Corticospinal inhibition on the side not to be moved implies that suppression of movement is an active process. This inhibition is more efficient for right- than for left-side movements in right-handed subjects, possibly because of left hemispheric dominance for movement.

The side effects of repetitive transcranial magnetic stimulation are largely unexplored and the limits of safe exposure have not been determined except as regards the acute production of seizures. Although tissue damage is unlikely, however, cognitive and other adverse effects have been observed and the possibility of unintended long-term changes in brain function are theoretically possible.

Five healthy volunteers were studied using interleaved transcranial magnetic stimulation/functional magnetic resonance imaging (TMS/fMRI) and an averaged single trial (AST) protocol. Blood oxygenation level-dependent (BOLD)-fMRI response to single TMS pulses over the motor cortex was detectable in both the ipsilateral motor cortex under the TMS coil and the contralateral motor cortex, as well as bilaterally in the auditory cortex. The associated BOLD signal increase showed the typical fMRI hemodynamic response time course. The brain's response to a single TMS pulse over the motor cortex at 120% of the level required to induce thumb movement (1.0%-1.5% signal increase) was comparable in both level and duration to the auditory cortex response to the sound accompanying the TMS pulse (1.5% -2.0% signal increase).

The potential uses for Transcranial Magnetic Stimulation (TMS) in the study of learning and memory range from a method to map the topography and intensity of motor output maps during visuomotor learning to inducing reversible lesions that allow for the precise temporal and spatial dissection of the brain processes underlying learning and remembering. Single-pulse TMS appears to be adequate to examine motor output maps but repetitive TMS (rTMS) appears necessary to affect most cognitive processes in measurable ways. The results we have reviewed in this article indicate that rTMS may have a potential clinical application in patients with epilepsy in whom it is important to identify the lateralization of verbal memory. Single-pulse TMS can help identify changes in motor output maps during training, that may indicate improved or diminished learning and memory processes following a stroke or other neurological insult. Other evidence indicates that rTMS may even have the capability of facilitating various aspects of memory performance. From a research perspective. rTMS has demonstrated site- and time-specific effects primarily in interfering with explicit retrieval of episodic information from long-term memory. rTMS may also be able to modulate retrieval from semantic memory as evidenced by response-time and accuracy changes after rTMS. All these findings suggest that the use of transcranial magnetic stimulation in the study of learning and memory will increase in the future and that it is already a valuable tool in the cognitive neuroscientists' belt.

1. Transcranial magnetic stimulation (TMS) of the human motor cortex results in multiple discharges (D and I waves) in the corticospinal tract. We tested whether these volleys can be explored non-invasively with paired TMS. The intensity of the first stimulus (S1) was set to produce a motor-evoked potential (MEP) of 1 mV in the resting contralateral abductor digiti minimi (ADM) muscle; the second stimulus (S2) was set to 90 % of the resting motor threshold. At interstimulus intervals of 1.1-1.5, 2.3-2.9 and 4.1-4.4 ms the MEP elicited by S1 plus S2 was larger than that produced by S1 alone. 2. Varying the S1 intensity between 70 and 130 % resting motor threshold with S2 held constant at 90 % resting motor threshold showed that the threshold for the first MEP peak was

Electrophysiological studies have shown that 1-Hz repetitive transcranial magnetic stimulation (rTMS) of the primary motor area (M1) can produce a local decrease in excitability. Functional imaging data suggest that this change may be bilateral. In normal subjects, we measured motor evoked potential (MEP) amplitude at a series of stimulation intensities in the contralateral M1 before and after 15 min of active or sham rTMS at just above the MEP threshold. The slope of the curve relating MEP amplitude and stimulation intensity was decreased in the unstimulated hemisphere by active but not sham rTMS. This demonstrates that rTMS can condition cortical excitability at a distance of one or more synapses and suggest that decreased excitability to TMS is a correlate of decreased blood flow and metabolism.

We attempted to map the representations of movements in 2 normal subjects by delivering five transcranial magnetic stimuli (TMS) with a focal coil to each of a grid of positions over the primary motor area (M1). Isometric forces were recorded from the contralateral index finger. Maps were made with the hand in a semiflexed “neutral” position, and with the thumb and index finger opposed in a “pincer” grip. The electromyogram (EMG) was monitored to ensure relaxation. The wrist was immobilized. In the neutral position, TMS at almost all positions produced abduction. Flexion was produced in the pincer position. Thus, while sensitive to changes in posture, TMS mapping may not be sensitive to the topographical organization of the M1 by movements as detected with direct cortical stimulation. Hum. Brain Mapping 6:390–393, 1998. © 1998 Wiley‐Liss, Inc.

To determine if linguistic processing could be selectively disrupted with repetitive transcranial magnetic stimulation (rTMS), rTMS was performed during a picture-word verification task. Seven right-handed subjects were trained in two conditions: picture-word verification, which required the subject to verify whether the picture of an object matched the subtitle name on the same page, and frame verification, which required subjects to verify whether there was a rectangular frame around the combined object picture and subtitle. Half of the trials were performed during rTMS. The effects of rTMS on performance were evaluated at the following four scalp positions: left anterior (the area where rTMS produced speech arrest), a mirror site on the right, and two positions in the left and right parietal region. Stimulation over the left deltoid muscle served as a control. Subjects had less difficulty in making picture-word matching decisions during unstimulated compared with stimulated trials at the left anterior and posterior positions. No significant difference in accuracy was detected in the frame verification condition, but response times in the frame verification condition were longer with stimulation at the left anterior position. Because rTMS of the dominant hemisphere affected linguistic processing independent of speech motor output, we confirm that rTMS may be used to investigate language and other cognitive functions.

Induction of a seizure in a normal subject with trains of repetitive transcranial magnetic stimulation (rTMS) applied in close succession suggested that short inter-train intervals, a parameter not considered in our previous safety studies, may not be safe. Here, we evaluate the safety of different inter-train intervals for rTMS in 10 healthy volunteers. Ten rTMS trains at 20 Hz for 1.6 s and a stimulus intensity of 110% of motor threshold (MT) were found to be safe at the inter-train interval of 5 s. However, inter-train intervals of 1 s or less were unsafe for trains of 20 Hz for 1.6 s and stimulus intensities higher than 100% of MT. Based on these results, we propose safety guidelines for inter-train intervals at different stimulus intensities. We also analyzed the stimulus parameters, used in 3 studies, that led to seizures in normal subjects. One seizure was due to short inter-train intervals, one was likely related to intense individual rTMS trains close to the limit of our previous safety recommendations, and one was likely due to a combination of these two factors. To provide an additional safety margin, we suggest reducing the duration for individual rTMS trains by 25% from our previous recommendations. Updated safety tables currently in use at our institution are provided.

Post-exercise facilitation and post-exercise depression are phenomena described in motor evoked potentials (MEPs) elicited to transcranial magnetic stimulation. Brief, non-fatiguing muscle activation produces post-exercise facilitation, and prolonged fatiguing muscle activation produces post-exercise depression. We studied 12 normal subjects to determine whether post-exercise depression occurs before fatigue is reached. We recorded MEPs from the resting extensor carpi radialis muscle after increasing the duration of isometric wrist extension, at 50% of maximum voluntary contraction, until the muscle fatigued. Fatigue was defined as the inability to maintain that force. The mean exercise duration before the muscle fatigued was 130 s, and post-exercise depression occurred only beyond 90 s of exercise. We conclude that post-exercise depression is detectable only after prolonged muscle activation.

We used paired transcranial magnetic stimulation (TMS) to evaluate inhibitory mechanisms in eight patients with writer's cramp during rest and isometric wrist extension. Both stimuli were 110% of the motor threshold; the interstimulus intervals (ISIs) were 20 to 200 ms in increments of 10 ms. Surface EMG was recorded from wrist extensors. In the symptomatic hemisphere, there was no significant difference in the amplitude of the test (second) motor evoked-potential (MEP) between patients and age-matched controls at rest. However, with voluntary muscle activation, inhibition of the test MEP by the conditioning MEP was significantly less in writer's cramp patients than in controls (p = 0.02). The difference was most prominent at ISIs of 60 to 80 ms in which inhibition is maximum. In the asymptomatic hemisphere, there was no significant difference between patients and controls in both rest and active conditions. The silent period was shorter in patients than controls on the symptomatic side (p = 0.003) but not on the asymptomatic side. We conclude that the inhibitory effects induced by magnetic stimulation are reduced in patients with writer's cramp, but only on the symptomatic side during muscle activation. This may relate to the overflow of muscle activity that characterizes this condition.

We compare the use of two-dimensional Laplacian smoothing splines and median polish kriging for an exploratory analysis of spatial data sets. Splines were developed originally for modelling a process with determinstic mean structure, while median polish kriging was developed for predicting a spatial random process. We review the fundamentals of both methods, including smoothing parameter selection for splines and variogram estimation and solving the kriging equations for median polish kriging. We demonstrate application of the methods on maps of muscle representations on the human motor cortex (cortical maps). After applying both methods to 20 cortical maps (left and right hemispheres on each of 10 subjects), we compare the fitted surfaces on the basis of predictive ability, aesthetic appeal, and ease of computation.

We studied the effects of transcranial electrical stimulation (TES) and transcranial magnetic stimulation (TMS), delivered at intensities below the threshold for evoking an electromyographic response, on the disynaptic and presynaptic phases of reciprocal inhibition in 8 healthy subjects. After TES, the H-reflex evoked in the flexor carpi radialis (FCR) muscle was strongly facilitated when the cortical stimulus was given 4.0-4.5 ms after the test stimulus (median nerve stimulus). TES reduced the disynaptic phase of reciprocal inhibition most strongly when the cortical stimulus followed the test stimulus by 3.0-3.5 ms. TES also reduced presynaptic inhibition, but with a time course that was identical to that of the facilitation of the uninhibited H-reflex. After subthreshold TMS, the facilitation of the H-reflex showed at least 2 peaks, one occurring when the cortical stimulus was given 2 ms after the test stimulus and the other when the cortical stimulus followed the test stimulus by 0.5 to -1.5 ms. The effects of TMS on the 2 phases of reciprocal inhibition were similar, and in both cases the disinhibitory effects had essentially the same time course as the facilitatory effect of TMS on the uninhibited H-reflex. The different effects of TES on the 2 phases of reciprocal inhibition provide evidence of the presynaptic nature of the second phase. The absence of a difference in the effect of TMS on the 2 phases could be due to the more temporally dispersed descending volley after TMS.

Repetitive transcranial magnetic stimulation (rTMS) is a relatively new technique for activating the cerebral cortex through the scalp and skull. By inducing electrical currents in the brain, rTMS is able to produce a variety of effects, including muscle twitching, changes in motor performance, disruption of cognitive and perceptual processes, and changes in mood. Although the technique is noninvasive and easily tolerated by patients and normal subjects, rTMS can produce epileptic seizures and, potentially, other undesirable effects on brain function. Further studies will be required to fully define the safe ranges of the stimulation parameters.

Recent advances in functional neuroimaging (including positron emission tomography, single-photon emission tomography, and fast magnetic resonance imaging) have allowed better understanding of the brain regions involved in regulating normal and pathological moods. Repetitive transcranial magnetic stimulation (rTMS) has the ability to stimulate or temporarily impair brain regions, which makes it a powerful tool for directly testing theories of the neurologic basis of mood regulation.

High-Definition transcranial Direct Current Stimulation (HD-tDCS) using specialized small electrodes has been proposed as a focal, non-invasive neuromodulatory technique. Here we provide the first evidence of a change in cortical excitability after HD-tDCS of the motor cortex, using TMS motor evoked potential (MEP) as the measure of excitability. Stimulation for 20 minutes at 1 mA with an anode centered over the hand area of the motor cortex and four surrounding return electrodes (anodal 4×1 montage) produced a significant increase in MEP amplitude and variability after stimulation, compared to sham stimulation. Stimulation was well tolerated by all subjects with adverse effects limited to transient sensation under the electrodes. A high-resolution computational model confirmed predictions of increased focality using the 4×1 HD tDCS montage compared to conventional tDCS. Simulations also indicated that variability in placement of the center electrode relative to the location of the target (central sulcus) could account for increasing variability. These results provide support for the careful use of this technique where focal tDCS is desired.

Transcranial Direct Current Stimulation (tDCS) is a non-invasive, low-cost, well-tolerated technique producing lasting modulation of cortical excitability. Behavioral and therapeutic outcomes of tDCS are linked to the targeted brain regions, but there is little evidence that current reaches the brain as intended. We aimed to: (1) validate a computational model for estimating cortical electric fields in human transcranial stimulation, and (2) assess the magnitude and spread of cortical electric field with a novel High-Definition tDCS (HD-tDCS) scalp montage using a 4 × 1-Ring electrode configuration. In three healthy adults, Transcranial Electrical Stimulation (TES) over primary motor cortex (M1) was delivered using the 4 × 1 montage (4 × cathode, surrounding a single central anode; montage radius ~ 3 cm) with sufficient intensity to elicit a discrete muscle twitch in the hand. The estimated current distribution in M1 was calculated using the individualized MRI-based model, and compared with the observed motor response across subjects. The response magnitude was quantified with stimulation over motor cortex as well as anterior and posterior to motor cortex. In each case the model data were consistent with the motor response across subjects. The estimated cortical electric fields with the 4 × 1 montage were compared (area, magnitude, direction) for TES and tDCS in each subject. We provide direct evidence in humans that TES with a 4 × 1-Ring configuration can activate motor cortex and that current does not substantially spread outside the stimulation area. Computational models predict that both TES and tDCS waveforms using the 4 × 1-Ring configuration generate electric fields in cortex with comparable gross current distribution, and preferentially directed normal (inward) currents. The agreement of modeling and experimental data for both current delivery and focality support the use of the HD-tDCS 4 × 1-Ring montage for cortically targeted neuromodulation.

The transcranial application of weak direct current (DC) to the brain is an effective neuromodulation technique that has had more than a century of experimental and therapeutic use. Focal DC brain polarization is now undergoing renewed interest, because of the wide acceptance of TMS as a research tool and candidate treatment for brain disorders. The effects of static electrical fields on cortical neurons in vivo have been known since the advent of intracellular recording. These effects are highly selective for neurons oriented longitudinally in the plane of the electric field. DC can enhance cognitive processes occurring in the treated area. The earliest clinical application of DC polarization was in the field of mood disorders. However, due to lack of temporal and spatial resolution, this technique does not appear particularly useful for exploring neurophysiological mechanisms.

The variable amplitude of motor cortex is a striking aspect of the muscle response to transcranial magnetic stimulation. It is easy to produce large motor-evoked potentials (MEPs) in some healthy subjects, while others' cortico-muscular pathways seem barely excitable, even by the strongest available stimuli. MEP amplitude and other measures also vary widely within individuals over time. The factors of these differences among and within individuals are age, gross anatomy of the individuals, genetic factors, and physiological differences associated with behavioural and other traits such as personality, conditions like migraine. The MEP varies over time within individuals at rest under laboratory conditions. These variations can be short term or long term. Differences among neurologically normal individuals have important implications for research using TMS. These differences open doors to new fields of study to neurophysiologists in the treatment and etiology of brain disease.

High-Definition transcranial Direct Current Stimulation (HD-tDCS) using specialized small electrodes has been proposed as a focal, non-invasive neuromodulatory technique. Here we provide the first evidence of a change in cortical excitability after HD-tDCS of the motor cortex, using TMS motor evoked potential (MEP) as the measure of excitability. Stimulation for 20 minutes at 1 mA with an anode centered over the hand area of the motor cortex and four surrounding return electrodes (anodal 4×1 montage) produced a significant increase in MEP amplitude and variability after stimulation, compared to sham stimulation. Stimulation was well tolerated by all subjects with adverse effects limited to transient sensation under the electrodes. A high-resolution computational model confirmed predictions of increased focality using the 4×1 HD tDCS montage compared to conventional tDCS. Simulations also indicated that variability in placement of the center electrode relative to the location of the target (central sulcus) could account for increasing variability. These results provide support for the careful use of this technique where focal tDCS is desired.

Apathy, common in neurological disorders, is defined as disinterest and loss of motivation, with a reduction in self-initiated activity. Research in diseased populations has shown that apathy is associated with variations in the volume of brain regions such as the anterior cingulate and the frontal lobes. The goal of this study was to determine the neural signatures of apathy in people with penetrating traumatic brain injuries (pTBIs), as to our knowledge, these have not been studied in this sample. We studied 176 male Vietnam War veterans with pTBIs using voxel-based lesion-symptom mapping (VLSM) and apathy scores from the UCLA Neuropsychiatric Inventory (NPI), a structured inventory of symptoms completed by a caregiver. Our results revealed that increased apathy symptoms were associated with brain damage in limbic and cortical areas of the left hemisphere including the anterior cingulate, inferior, middle, and superior frontal regions, insula, and supplementary motor area. Our results are consistent with the literature, and extend them to people with focal pTBI. Apathy is a significant symptom since it can reduce participation of the patient in family and other social interactions, and diminish affective decision-making.

We present a Near-infra red handheld device for imaging subsurface hemorrhage such as hematomas. The device uses novel motion-based measurement techniques to detect inclusions in real-time. We present phantom studies to demonstrate the technique.

In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 frontotemporal lobar degeneration (FTLD) patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-frontotemporal dementia (FTD) and 2 FTD-amyotrophic lateral sclerosis [ALS]) out of 53 patients and 1 neurologically normal control. Interestingly, 2 of the C9ORF72 expansion carriers also carried 2 novel missense mutations in GRN (Y294C) and in PSEN-2(I146V). Further, 1 of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to TAR (trans-activation response) DNA-binding protein (TDP)-43 pathology. In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD, or FTD-ALS and occasional comorbid conditions such as Alzheimer's disease. These findings are novel and need to be cautiously interpreted and most importantly replicated in larger numbers of samples.

We construct a normative database for a simple cognitive test which can be useful in evaluating cognitive disability such as mild traumatic brain injury. Our results with fNIRS show activation from the medial frontopolar cortex

We studied the effects of transcranial motor cortex stimulation on the electromyographic characteristics of tremor in 9 patients with familial essential tremor and in 12 patients with postural tremor associated with Parkinson's disease. Transcranial magnetic stimulation reset both types of tremor equally. The resetting depended on the stimulus intensity, but was most closely correlated with the duration of the electromyographic silent period that followed the stimulus-induced motor evoked potential. Tremor resetting was present bilaterally even after focal, unilateral stimulation. Transcranial electrical stimulation failed to reset the tremor in either patient group. These results emphasize the role of central, intracortical structures in the generation of essential tremor and postural tremor in Parkinson's disease. © 1994 John Wiley & Sons, Inc.

We applied trains of focal, rapid-rate transcranial magnetic stimulation (rTMS) to the motor cortex of 14 healthy volunteers with recording of the EMG from the contralateral abductor pollicis brevis, extensor carpi radialis, biceps brachii and deltoid muscles. Modulation of the amplitude of motor evoked potentials (MEPs) produced in the target muscle during rTMS showed a pattern of inhibitory and excitatory effects which depended on the rTMS frequency and intensity. With the magnetic coil situated over the optimal scalp position for activating the abductor pollicis brevis, rTMS led to spread of excitation, as evident from the induction of progressively larger MEPs in the other muscles. The number of pulses inducing this spread of excitation decreased with increasing rTMS frequency and intensity. Latency of the MEPs produced in the other muscles during the spread of excitation was significantly longer than that produced by single-pulse TMS applied to the optimal scalp positions for their activation. The difference in MEP latency could be explained by a delay in intracortical conduction along myelinated cortico-cortical pathways. Following rTMS, a 3-4 min period of increased excitability was demonstrated by an increase in the amplitude of MEPs produced in the target muscles by single-pulse TMS. Nevertheless, repeated rTMS trains applied 1 min apart led to similar modulation of the responses and to spread of excitation after approximately the same number of pulses. This suggests that the spread might be due to the breakdown of inhibitory connections or the recruitment of excitatory pathways, whereas the post-stimulation facilitation may be due to a transient increase in the efficacy of excitatory synapses.

Anxiety negatively affects quality of life and psychosocial functioning. Previous research has shown that anxiety symptoms in healthy individuals are associated with variations in the volume of brain regions, such as the amygdala, hippocampus, and the bed nucleus of the stria terminalis. Brain lesion data also suggests the hemisphere damaged may affect levels of anxiety. We studied a sample of 182 male Vietnam War veterans with penetrating brain injuries, using a semi-automated voxel-based lesion-symptom mapping (VLSM) approach. VLSM reveals significant associations between a symptom such as anxiety and the location of brain lesions, and does not require a broad, subjective assignment of patients into categories based on lesion location. We found that lesioned brain regions in cortical and limbic areas of the left hemisphere, including middle, inferior and superior temporal lobe, hippocampus, and fusiform regions, along with smaller areas in the inferior occipital lobe, parahippocampus, amygdala, and insula, were associated with increased anxiety symptoms as measured by the Neurobehavioral Rating Scale (NRS). These results were corroborated by similar findings using Neuropsychiatric Inventory (NPI) anxiety scores, which supports these regions' role in regulating anxiety. In summary, using a semi-automated analysis tool, we detected an effect of focal brain damage on the presentation of anxiety. We also separated the effects of brain injury and war experience by including a control group of combat veterans without brain injury. We compared this control group against veterans with brain lesions in areas associated with anxiety, and against veterans with lesions only in other brain areas.

Since its commercial advent in 1985, transcranial magnetic stimulation (TMS), a technique for stimulating neurons in the cerebral cortex through the scalp, safely and with minimal discomfort, has captured the imaginations of scientists, clinicians and lay observers. Initially a laboratory tool for neurophysiologists studying the human motor system, TMS now has a growing list of applications in clinical and basic neuroscience. Although we understand many of its effects at the system level, detailed knowledge of its actions, particularly as a modulator of neural activity, has lagged, due mainly to the lack of suitable non-human models. Nevertheless, these gaps have not blocked the therapeutic application of TMS in brain disorders. Moderate success has been achieved in treating disorders such as depression, where the U.S. Food and Drug Administration has cleared a TMS system for therapeutic use. In addition, there are small, but promising, bodies of data on the treatment of schizophrenic auditory hallucinations, tinnitus, anxiety disorders, neurodegenerative diseases, hemiparesis, and pain syndromes. Some other nascent areas of study also exist. While the fate of TMS as a therapeutic modality depends on continued innovation and experimentation, economic and other factors may be decisive.

This study aimed to evaluate genetic variability in the FUS and TDP-43 genes, known to be mainly associated with amyotrophic lateral sclerosis (ALS), in patients with the diagnoses of frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS). We screened the DNA of 228 patients for all the exons and flanking introns of FUS and TDP-43 genes. We identified 2 novel heterozygous missense mutations in FUS: P106L (g.22508384C>T) in a patient with behavioral variant frontotemporal dementia (bvFTD) and Q179H in several members of a family with behavioral variant FTD. We also identified the N267S mutation in TDP-43 in a CBS patient, previously only reported in 1 ALS family and 1 FTD patient. Additionally, we identified 2 previously reported heterozygous insertion and deletion mutations in Exon 5 of FUS; Gly174-Gly175 del GG (g. 4180-4185 delGAGGTG) in an FTD patient and Gly175-Gly176 ins GG (g. 4185-4186 insGAGGTG) in a patient with diagnosis of CBS. Not least, we have found a series of variants in FUS also in neurologically normal controls. In summary, we report that genetic variability in FUS and TDP-43 encompasses a wide range of phenotypes (including ALS, FTD, and CBS) and that there is substantial genetic variability in FUS gene in neurologically normal controls.

We studied the excitatory motor evoked potentials (MEPs) and the inhibitory (silent period) responses to focal transcranial magnetic stimulation (TMS) in the abductor pollicis brevis (APB) of 5 normal subjects to learn whether the scalp topography of the two responses differed. At the scalp location where stimulation produced the highest-amplitude MEP in the voluntarily activated APB, stimulus intensities below the MEP threshold produced silent periods with little or no preceding facilitation. The silent periods had a mean duration of 26.8 +/- 6.8 msec and a mean onset latency of 27.6 +/- 3.6 msec, which was 7.2 +/- 2.3 msec longer than the latency of MEPs produced in the APB by higher stimulus intensities. A period of excitation, with an onset latency of 50-80 msec, often followed the silent period. On averaged trials, a stimulus intensity just above the threshold of the MEP at its optimal position produced MEPs followed by silent periods at a cluster of scalp locations 1 cm apart on the central scalp (medial area) and silent periods with very slight or no preceding facilitation in 3-9 locations lateral to the MEP area (lateral area). This finding was confirmed in 3 subjects with maps constructed from statistical analysis of multiple trials. These maps also showed that MEPs produced from the medial area occurred 4-6 msec earlier than those produced from the lateral area. The integral of the silent period tended to be larger in the lateral area. The motor representation of APB, as defined by TMS, is not homogeneous but rather contains at least two components that differ physiologically and topographically.

Summary In humans, training in which good performance is rewarded or bad performance punished results in transient behavioral improvements [1–3]. The relative effects of reward and punishment on consolidation and long-term retention, critical behavioral stages for successful learning [4, 5], are not known. Here, we investigated the effects of reward and punishment on these different stages of human motor skill learning. We studied healthy subjects who trained on a motor task under rewarded, punished, or neutral control conditions. Performance was tested before and immediately, 6 hr, 24 hr, and 30 days after training in the absence of reward or punishment. Performance improvements immediately after training were comparable in the three groups. At 6 hr, the rewarded group maintained performance gains, whereas the other two groups experienced significant forgetting. At 24 hr, the reward group showed significant offline (posttraining) improvements, whereas the other two groups did not. At 30 days, the rewarded group retained the gains identified at 24 hr, whereas the other two groups experienced significant forgetting. We conclude that training under rewarded conditions is more effective than training under punished or neutral conditions in eliciting lasting motor learning, an advantage driven by offline memory gains that persist over time.

We used transcranial magnetic stimulation to map the cortical representations of 4 upper extremity muscles (abductor pollicis brevis, flexor carpi radialis, biceps, and deltoid) of 10 normal subjects. Three stimuli were delivered to scalp positions 1 cm apart, and the amplitude and latency of the motor evoked potentials (MEPs) were averaged for each position. Maps were described in terms of number of excitable scalp positions, amplitude of MEPs, scalp positions for evoking largest amplitude MEPs, and threshold for producing MEPs. We compared different muscles across subjects and the same muscles on the left and right sides in individual subjects. Distal muscles had larger representations with higher amplitude MEPs and lower thresholds. Biceps and deltoid on the left had larger representations and higher MEP amplitudes than on the right. Maps showed a somatotopic progression on the scalp of proximal to distal muscles along a posteromedial to anterolateral axis.

Objective To determine the brain areas associated with specific components of ideomotor apraxia (IMA) in corticobasal syndrome (CBS). Design Case-control and cross-sectional study. Participants Forty-eight patients with CBS and 14 control subjects. Intervention Administration of the Test of Oral and Limb Apraxia. Main Outcome Measures Differences between patients with CBS and healthy controls and associations between areas of gray matter volume and IMA determined by voxel-based morphometry in patients with CBS. Results Overall, IMA was associated with decreased gray matter volume in the left supplemental motor area, premotor cortex, and caudate nucleus of patients with CBS. The overall degree of apraxia was independent of the side of motor impairment. Praxis to imitation (vs command) was particularly impaired in the patients with CBS. Patients demonstrated equal impairment in transitive and intransitive praxis. Conclusions In patients with CBS, IMA is associated with left posterior frontal cortical and subcortical volume loss. Despite showing left frontal volume loss associated with IMA, patients with CBS have particularly impaired imitation of gestures. These findings suggest either that the IMA of CBS affects a route of praxis that bypasses motor engrams or that motor engrams are affected but that they exist in areas other than the inferior parietal cortex.

Working memory (WM) has been described as short-term retention of information that is no longer accessible in the environment, and the manipulation of this information for subsequent use in guiding behavior. WM is viewed as a cognitive process underlying higher-order cognitive functions. Evidence supports a critical role for PFC in mediating WM performance. Studies show psychomotor processing speed and accuracy account for considerable variance in neural efficiency (Ne). This study compared the relative effects of active and sham 10 Hz rTMS applied to dorsolateral prefrontal cortex (DLPFC) on indices of Ne in healthy participants performing a WM paradigm that models the association between WM load and task behavior [Sternberg, S. High-speed scanning in human memory. Science, 153, 652–654, 1966]. Previous studies identified a relationship between diminished Ne and impaired WM across a broad array of clinical disorders. In the present study, the authors predicted there would be a main effect of stimulation group (STM) on accuracy (SCR) and processing speed (RT), hence, Ne. We observed a main effect of STM for RT without an effect on SCR; even so, there was a robust effect of STM on Ne.

Frontotemporal dementia (FTD) is a progressive neurodegenerative disease that primarily affects the frontal and anterior temporal lobes, resulting in changes in behavior, language, and cognition.1 Corticobasal syndrome (CBS) is a disorder characterized by progressive asymmetric apraxia and rigidity with other findings of cortical (e.g., alien limb, cortical sensory loss, myoclonus) and basal ganglia (e.g., bradykinesia and increased resistance to passive movement) dysfunction.2,3 Both disorders can be associated with pathologic tau aggregation.1–5 Patients with FTD and patients with CBS often have deficits in executive function,6–9 a term that encompasses complex cognitive functions such as planning, judgment, reasoning, problem solving, organization, attention, abstraction, and mental flexibility.10 Several questions, however, remain unanswered: How do the patterns of executive dysfunction of behavioral variant FTD (bv-FTD) and CBS compare? What brain areas are associated with specific symptoms of executive dysfunction in bv-FTD and CBS? These are important questions for several reasons: executive dysfunction is a clinically important symptom in FTD11 and CBS,7 but little is known about its neurobiological basis in these disorders; and insights from patients with deficits in executive function can elucidate the neuroanatomic basis of executive function in healthy people. The distributions of atrophy observed in FTD and CBS are ideal to determine the relative contributions of regions of the frontal and parietal cortexes to executive function. A review of the brain areas involved in the performance of executive function tests is beyond the scope of this article, but in summary, while intact executive function requires more fundamental cognitive abilities in other parts of the brain (including the parietal lobe12), the prefrontal cortex, especially on the left, is prominently associated with executive functions.13 Patients with FTD had high numbers of rule violations on the Tower Test compared to patients with Alzheimer disease and healthy controls,14 and impaired performance on a sorting task associated with decreased left frontal lobe volume.15 Performance on the Twenty Questions test has been shown to be impaired in patients with prefrontal cortex lesions,16 and letter fluency is impaired in patients with left prefrontal17 lesions. Patients with FTD who had progressive disease were especially impaired on digit span and inhibition of prepotent responses.18 The Delis-Kaplan Executive Function System (D-KEFS) is a battery of nine standardized executive function tests (Trail Making, Verbal Fluency, Design Fluency, Color-Word Interference, Sorting, Twenty Questions, Word Context, Tower, and Proverb interpretation) designed to comprehensively assess higher cognitive function.19 In this study, we compared D-KEFS scores between the patients with CBS and patients with FTD and determined which areas of the brain are associated with these executive functions using voxel-based morphometry (VBM) of MRI. Based on the findings discussed above and the brain areas affected in FTD and CBS, we hypothesized that patients with FTD would show more severe executive dysfunction than the patients with CBS and that this executive dysfunction would be associated with left prefrontal atrophy in the patients with FTD and left prefrontal and parietal atrophy in the patients with CBS.

At least four forms of functional neuroplasticity can be studied in patients recovering from brain damage and normal volunteers: (1) homologous area adaptation, (2) cross-modal reassignment, (3) potentiation of topographic representations, and (4) compensatory masquerade. Homologous area adaptation is the assumption of an anatomically predetermined role (e.g., language expression) by the homologous region in the opposite cerebral hemisphere. Cross-modal reassignment occurs when structures previously devoted to processing a particular kind of sensory input begin to process input from a new sensory modality. Potentiation of topographic representations is the topographic modulation of a functional brain region with repeated performance or experience. Compensatory masquerade is the adaptation of a preexisting process to a new behavioral role. By focusing on these four forms of functional neuroplasticity, several fundamental questions about how recovery of function occurs after brain damage can be addressed.

Summary Basic principles of magnetic stimulation of biological tissues are reviewed. Noninvasive magnetic stimulation of the brain delivered over sensorimotor areas evokes movements and less commonly paresthesias in contralateral limbs. We have evaluated the maps of motor outputs in patients with (1) congenital mirror movements, which resulted in marked derangement of the map of outputs of distal hand muscles with enlarged and ipsilateral representations; (2) amputations, which resulted in plastic reorganization of motor outputs targeting muscles immediately proximal to the stump; (3) spinal cord injury, which also resulted in enlargement of the map of outputs targeting muscles proximal to the lesion level; and (4) hemispherectomy performed at an early age for intractable seizures, which resulted in the remaining hemisphere controlling ipsilateral arm muscles. These results demonstrate the potential for reorganization in motor systems following lesions in the peripheral as well as in the central nervous system.

Optimal parameters of rTMS for antidepressant efficacy in general, or within patients, have not been adequately delineated.Using a double-blind, sham-controlled, cross-over design, 22 adult patients with treatment refractory major depression (n=9; bipolar disorder, depressed phase) were randomized to active rTMS (20-Hz or 1-Hz) or sham rTMS conditions and given 5 rTMS treatments per week for two weeks. Repetitive TMS was administered at 100% of motor threshold for 1600 pulses over the left prefrontal cortex using a figure-eight coil. Patients initially randomized to sham rTMS were then exposed to two weeks of active rTMS with each frequency under blinded conditions. Those who received active 20-Hz and 1-Hz rTMS were crossed over to the opposite frequency for two weeks. Improvement in Hamilton Depression ratings were assessed after each two-week treatment phase. PET imaging was used to evaluate the patient's baseline absolute regional cerebral activity (blood flow and metabolism) as potential predictor of clinical response.Changes in depression severity on 1-Hz and 20-Hz rTMS were inversely correlated. PET scans with baseline hypoperfusion (but not hypometabolism) were associated with better improvement on 20-Hz rTMS as predicted.The magnitude of the clinical change with either frequency at 100% motor threshold was not robust, and larger studies with higher intensities of rTMS for longer durations of time should be explored.High and low frequency rTMS exerts differential effects on depressed mood within individual subjects. The brain activity predictors and correlates of an optimal antidepressant response to rTMS remain to be better defined.

Objective There has been no modern effort to replicate, further characterize, or quantify the dramatic effects on affect described in controlled studies from the 1960s using bilateral frontal electrodes with an extra-cephalic reference in a mixed group composed primarily of mildly depressed individuals. We performed a comprehensive, quantitative assessment of the effects of bifrontal TDCS on emotion in 21 healthy subjects. Methods In a double-blind crossover study, we administered tests of emotional state, affect, emotional decision-making, arousal, and psychomotor functions during sham, anodal, and cathodal TDCS. Results We found no systematic effects on any measure, despite two subjects who had pronounced mood effects in the predicted direction. There were no adverse events. Conclusions In line with some other studies, we found no consistent effects of bifrontal TDCS on measures of emotional function of psychomotor performance. Significance These results demonstrate the safety of bilateral anterior frontal TDCS with an extra-cephalic reference, but raise questions about its effectiveness as a modulator of mood and emotional cognition, at least in healthy subjects.