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1.  Transcranial Magnetic Brain Stimulation: Therapeutic Promises and Scientific Gaps 
Pharmacology & therapeutics  2011;133(1):98-107.
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.
PMCID: PMC3241868  PMID: 21924290
Brain stimulation; neuromodulation; neurology; psychiatry; depression
2.  Injured Brain Regions Associated with Anxiety in Vietnam Veterans 
Neuropsychologia  2013;51(4):686-694.
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.
PMCID: PMC3644343  PMID: 23328629
anxiety; traumatic brain injury; voxel-based lesion symptom mapping
4.  Transcranial Direct Current Stimulation for the Treatment of Parkinson’s Disease 
Progression of Parkinson’s disease (PD) is characterized by motor deficits, which eventually respond less to dopaminergic therapy and, thus, pose a therapeutic challenge. Deep brain stimulation has proven efficacy, but carries risks and is not possible in all patients. Non-invasive brain stimulation has shown promising results and may provide a therapeutic alternative.
To investigate the efficacy of transcranial direct current stimulation (tDCS) in the treatment of PD
Randomized, double blind, sham-controlled study.
Research institution
We investigated efficacy of anodal tDCS applied to the motor and prefrontal cortices in 8 sessions over 2.5 weeks. Assessment over a 3-month period included timed tests of gait (primary outcome measure) and bradykinesia in the upper extremities, UPDRS, Serial Reaction Time Task, Beck Depression Inventory, Health Survey and self-assessment of mobility.
Twenty-five PD patients were investigated, 13 receiving tDCS and 12 sham stimulation. TDCS improved gait by some measures for a short time and improved bradykinesia in both the on- and off-states for longer than 3 months. Changes in UPDRS, reaction time, physical and mental well-being, and self-assessed mobility did not differ between tDCS and sham intervention.
TDCS of the motor and prefrontal cortices may have therapeutic potential in PD, but better stimulation parameters need to be established to make the technique clinically viable.
PMCID: PMC4162743  PMID: 20870863
transcranial direct current stimulation (tDCS); non-invasive brain stimulation; therapeutic study; Parkinson’s disease
5.  Tolerability of transcranial Direct Current Stimulation in Childhood-Onset Schizophrenia 
Brain stimulation  2011;4(4):275-280.
In recent years, transcranial direct current stimulation (tDCS) has been used to study and treat many neuropsychiatric conditions. However, information regarding its tolerability in the pediatric population is lacking.
This study aims to investigate the tolerability aspects of tDCS in the childhood-onset schizophrenia (COS) population.
Twelve participants with COS completed this inpatient study. Participants were assigned to one of two groups: bilateral anodal dorsolateral prefrontal cortex (DLPFC) stimulation (n= 8) or bilateral cathodal superior temporal gyrus (STG) stimulation (n=5). Patients received either 2 mA of active treatment or sham treatment (with possibility of open active treatment) for 20 minutes, for a total of 10 sessions (2 weeks).
tDCS was well tolerated in the COS population with no serious adverse events occurring during the study.
This is the first study to demonstrate that a 20 minute duration of 2 mA of bilateral anodal and bilateral cathodal DC polarization to the DLPFC and STG was well tolerated in a pediatric population.
PMCID: PMC3204188  PMID: 22032743
dorsolateral prefrontal cortex; transcranial direct current stimulation; childhood-onset schizophrenia
6.  Transcranial magnetic stimulation in Clinical Pharmacology 
Transcranial magnetic stimulation (TMS) is a safe and easy technique for stimulating neurons in the human central nervous system. Studies combining TMS with drugs in healthy subjects and patients have advanced our knowledge of how TMS activates brain circuits and led to new techniques for evaluating the function of specific systems. For example, TMS techniques can detect effects on axon membranes, glutamatergic and GABAergic synapses and the influence of catecholaminergic systems, as well as group differences due to genetic variations in the response to drugs. With this knowledge base, TMS can now be used to explore and compare the effects of drugs on brain systems and may also serve as a surrogate for behavioral responses in clinical trials.
PMCID: PMC2613312  PMID: 19122782
Transcranial Magnetic Stimulation; Single Pulse; Transcranial Magnetic Stimulation; Paired Pulse; Drug Physiological Effects; Neurotransmitter Agents; GABA; Glutamate; Monoamines; Biogenic
7.  Reward processing abnormalities in Parkinson disease 
The primary motor cortex is important for motor learning and response selection, functions that require information on the expected and actual outcomes of behavior. Therefore, it should receive signals related to reward and pathways from reward centers to motor cortex exist in primates. Previously, we showed that gamma aminobutyric acid-A(GABAA)-mediated inhibition in motor cortex, measured by paired transcranial magnetic stimulation (TMS), changes with expectation and uncertainty of money rewards generated by a slot machine simulation.
We examined the role of dopamine in this phenomenon by testing 13 mildly affected Parkinson disease patients, off and on dopaminergic medications, and 13 healthy, age-matched controls.
Consistent with a dopaminergic mechanism, reward expectation or predictability modulated the response to paired TMS in controls, but not in unmedicated patients. A single dose of pramipexole restored this effect of reward, mainly by increasing the paired TMS response amplitude during low expectation. Levodopa produced no such effect. Both pramipexole and levodopa increased risk-taking behavior on the Iowa Gambling Task. However, pramipexole increased risk-taking behavior more in patients showing lower paired TMS response amplitude during low expectation.
These results provide evidence that modulation of motor cortex inhibition by reward is mediated by dopamine signaling and that physiological states in the motor cortex are associated with levels of risk-taking behavior in patients on pramipexole. The cortical response to reward expectation may represent an endophenotype for risk-taking behavior in patients on agonist treatment.
PMCID: PMC3150632  PMID: 21538525
Transcranial magnetic stimulation (TMS); dopamine; gambling; motor cortex
8.  Screening for C9ORF72 repeat expansion in FTLD 
Neurobiology of aging  2012;33(8):1850.e1-1850.11.
In the present study we aimed to determine the prevalence of C9ORF72 GGGGCC hexanucleotide expansion in our cohort of 53 FTLD patients and 174 neurologically normal controls. We identified the hexanucleotide repeat, in the pathogenic range, in 4 (2 bv-FTD and 2 FTD-ALS) out of 53 patients and one neurologically normal control. Interestingly, two of the C9ORF72 expansion carriers also carried two novel missense mutations in GRN (Y294C) and in PSEN-2 (I146V). Further, one of the C9ORF72 expansion carriers, for whom pathology was available, showed amyloid plaques and tangles in addition to 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.
PMCID: PMC3743244  PMID: 22459598
FTLD; bv-FTD; FTD-ALS; C9ORF72; GRN; PSEN-2; Alzheimer’s disease
9.  Normative database of judgment of complexity task with functional near infrared spectroscopy – Application for TBI 
Neuroimage  2012;60(2):879-883.
The ability to assess frontal lobe function in a rapid, objective, and standardized way, without the need for expertise in cognitive test administration might be particularly helpful in mild traumatic brain injury (TBI), where objective measures are needed. Functional near infrared spectroscopy (fNIRS) is a reliable technique to noninvasively measure local hemodynamic changes in brain areas near the head surface. In this paper, we are combining fNIRS and frameless stereotaxy which allowed us to co-register the functional images with previously acquired anatomical MRI volumes. In our experiment, the subjects were asked to perform a task, evaluating the complexity of daily life activities, previously shown with fMRI to activate areas of the anterior frontal cortex. We reconstructed averaged oxyhemoglobin and deoxyhemoglobin data from 20 healthy subjects in spherical coordinate. The spherical coordinate is a natural representation of surface brain activation projection. Our results show surface activation projected from the medial frontopolar cortex which is consistent with previous fMRI results. With this original technique, we will construct a normative database for a simple cognitive test which can be useful in evaluating cognitive disability such as mild traumatic brain injury.
PMCID: PMC3303953  PMID: 22306800
Near infrared spectroscopy; frameless stereotaxy; frontal cortex; group study
10.  TDCS Guided using fMRI Significantly Accelerates Learning to Identify Concealed Objects 
Neuroimage  2010;59(1):117-128.
The accurate identification of obscured and concealed objects in complex environments was an important skill required for survival during human evolution, and is required today for many forms of expertise. Here we used transcranial direct current stimulation (tDCS) guided using neuroimaging to increase learning rate in a novel, minimally guided discovery-learning paradigm. Ninety-six subjects identified threat-related objects concealed in naturalistic virtual surroundings used in real-world training. A variety of brain networks were found using fMRI data collected at different stages of learning, with two of these networks focused in right inferior frontal and right parietal cortex. Anodal 2.0 mA tDCS performed for 30 minutes over these regions in a series of single-blind, randomized studies resulted in significant improvements in learning and performance compared with 0.1 mA tDCS. This difference in performance increased to a factor of two after a one-hour delay. A dose-response effect of current strength on learning was also found. Taken together, these brain imaging and stimulation studies suggest that right frontal and parietal cortex are involved in learning to identify concealed objects in naturalistic surroundings. Furthermore, they suggest that the application of anodal tDCS over these regions can greatly increase learning, resulting in one of the largest effects on learning yet reported. The methods developed here may be useful to decrease the time required to attain expertise in a variety of settings.
PMCID: PMC3387543  PMID: 21094258
Perception; Attention; Memory; Functional Magnetic Resonance Imaging; Expertise; Training; Transcranial Direct Current Stimulation; Frontal Cortex; Parietal Cortex; Medial Temporal Lobe; Cingulate Cortex
11.  Reward improves long-term retention of a motor memory through induction of offline memory gains 
Current biology : CB  2011;21(7):557-562.
In humans, training in which good performance is rewarded or bad performance punished results in transient behavioral improvements [1–3]. Their relative effects 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 hs, 24 hs 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 hs, the rewarded group maintained performance gains while the other two groups experienced significant forgetting. At 24 hs, the reward group showed significant offline (posttraining) improvements while the other two groups did not. At 30 days, the rewarded group retained the gains identified at 24 hs, while 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.
PMCID: PMC3075334  PMID: 21419628
12.  A hematoma detector—a practical application of instrumental motion as signal in near infra-red imaging 
Biomedical Optics Express  2011;3(1):192-205.
Abstract: In this paper we discuss results based on using instrumental motion as a signal rather than treating it as noise in Near Infra-Red (NIR) imaging. As a practical application to demonstrate this approach we show the design of a novel NIR hematoma detection device. The proposed device is based on a simplified single source configuration with a dual separation detector array and uses motion as a signal for detecting changes in blood volume in the dural regions of the head. The rapid triage of hematomas in the emergency room will lead to improved use of more sophisticated/expensive imaging facilities such as CT/MRI units. We present simulation results demonstrating the viability of such a device and initial phantom results from a proof of principle device. The results demonstrate excellent localization of inclusions as well as good quantitative comparisons.
PMCID: PMC3255337  PMID: 22254179
(110.3080) Infrared imaging; (170.3880) Medical and biological imaging
13.  Characteristics of Frontotemporal Dementia Patients with a Progranulin Mutation 
Annals of neurology  2006;60(3):374-380.
Mutations in the Progranulin gene (PGRN) recently have been discovered to be associated with frontotemporal dementia (FTD) linked to 17q21 without identified MAPT mutations. The range of mutations of PGRN that can result in the FTD phenotype and the clinical presentation of patients with PGRN mutations have yet to be determined.
In this study, we examined 84 FTD patients from families not known previously to have illness linked to chromosome 17 for identified PGRN and MAPT mutations and sequenced the coding exons and the flanking intronic regions of PGRN. We compared the prevalence, clinical characteristics, magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography results, and neuropsychological testing of patients with the PGRN R493X mutation with those patients without identified PGRN mutations.
We discovered a new PGRN mutation (R493X) resulting in a stop codon in two patients. This was the only PGRN mutation identified in our sample. The patients with the PGRN R493X mutation had a rapid illness course and had predominant right-sided atrophy and hypometabolism on magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography. The affected father of one of the patients with the PGRN R493X mutation showed frontal and temporal atrophy without neurofibrillary tangles on neuropathological examination.
Known PGRN and MAPT mutations were rare and of similar prevalence in our sample (2 compared with 1/84). The patients with the PGRN R493X mutation had a clinical presentation comparable with other behavior-predominant FTD patients. The neuropathology of an affected family member of a patient with the PGRN R493X mutation appears not to be Alzheimer’s disease.
PMCID: PMC2987739  PMID: 16983677
14.  Association of Ideomotor Apraxia With Frontal Gray Matter Volume Loss in Corticobasal Syndrome 
Archives of neurology  2009;66(10):1274-1280.
To determine the brain areas associated with specific components of ideomotor apraxia (IMA) in corticobasal syndrome (CBS).
Case-control and cross-sectional study.
Forty-eight patients with CBS and 14 control subjects.
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.
Overall, IMA was associated with decreased gray matter volume in the left supplemental motor area, pre-motor 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.
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.
PMCID: PMC2981036  PMID: 19822784
16.  Atomoxetine Treatment of ADHD in Tourette Syndrome: Reduction in Motor Cortex Inhibition Correlates with Clinical Improvement 
In children with Attention Deficit Hyperactivity Disorder (ADHD), clinical responses to the selective norepinephrine reuptake inhibitor atomoxetine (ATX) vary. We sought to determine in children with Tourette Syndrome (TS) whether clinical responses correlate with changes in short interval cortical inhibition (SICI).
Fourteen children, ages 8 to 16, with ADHD and TS were treated open-label with ATX for one month. ADHD rating scale scores and SICI, measured with paired-pulse Transcranial Magnetic Stimulation (pTMS), were assessed blindly and independently at treatment onset and one month later.
Eleven children, mean ADHD Rating Scale scores 31.8 (SD 8.2) at onset completed the study. After one month, ADHDRS changes ranged from an increase of 4 points to a decrease (improvement) of 24 points (mean change -9.6, SD 9.1). The changes in ADHDRS scores correlated with reduction in SICI (r = .74, p = .010).
In children with TS, one month of atomoxetine treatment appears to induce correlated improvements in ADHD and, paradoxically, further reductions in cortical inhibition.
PTMS-evoked SICI in ADHD with TS may be a biomarker of both deficiency and compensatory changes within cortical interneuronal systems. Effective atomoxetine treatment may augment compensatory processes and thereby reduce SICI.
PMCID: PMC1978200  PMID: 17588810
Cortical inhibition; transcranial magnetic stimulation; Attention Deficit Hyperactivity Disorder; Tourette Syndrome; atomoxetine
17.  In vivo and Postmortem Clinicoanatomical Correlations in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 
Neuro-Degenerative Diseases  2008;5(3-4):215-217.
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is associated with mutations in the Microtubule-Associated Protein Tau(MAPT) gene or the Progranulin(PGRN) gene. MAPT mutations lead to widespread deposition of hyperphosphorylated tau protein (FTDP-17T). PGRN mutations are associated with ubiquitin- and TDP-43-positive inclusions in the frontotemporal cortex, striatum and hippocampus (FTDP-17U). Despite the differences, FTDP-17T and FTDP-17U share a largely overlapping clinical phenotype.
To determine whether neuroimaging studies may allow an in vivo early differentiation between FTDP-17T and FTDP-17U.
We studied 25 individuals affected with FTDP-17T associated with either the exon 10+3 (24 subjects) or the G335S (1 subject) MAPT mutation, as well as 3 FTDP-17U individuals, who were carriers of the A9D, IVS6-2A>G or R493X PGRN mutation. Neuroimaging studies, obtained along the course of the disease, were compared to the neuropathologic findings.
FTDP-17T cases were associated with symmetric frontotemporal atrophy. Behavioral changes constituted the predominant clinical presentation. Conversely, an asymmetric degenerative process was seen in all 3 PGRN cases, who presented with either corticobasal syndrome (A9D) or frontotemporal dementia and language deterioration (IVS6-2A>G and R493X).
Neuroimaging data, in the early disease stage of FTDP-17, may offer the possibility of an early differentiation of FTDP-17T and FTDP-17U phenotypes, independent of the genetic analysis.
PMCID: PMC2826454  PMID: 18322394
Frontotemporal dementia and parkinsonism linked to chromosome 17; Tau; Ubiquitin; TDP-43; Neuropathology
18.  Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD 
BMC Neurology  2006;6:44.
A new locus for amyotrophic lateral sclerosis – frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p.
We identified chromosome 9p segregating haplotypes within two families with ALS-FTD (F476 and F2) and undertook mutational screening of candidate genes within this locus.
Candidate gene sequencing at this locus revealed the presence of a disease segregating stop mutation (Q342X) in the intraflagellar transport 74 (IFT74) gene in family 476 (F476), but no mutation was detected within IFT74 in family 2 (F2). While neither family was sufficiently informative to definitively implicate or exclude IFT74 mutations as a cause of chromosome 9-linked ALS-FTD, the nature of the mutation observed within F476 (predicted to truncate the protein by 258 amino acids) led us to sequence the open reading frame of this gene in a large number of ALS and FTD cases (n = 420). An additional sequence variant (G58D) was found in a case of sporadic semantic dementia. I55L sequence variants were found in three other unrelated affected individuals, but this was also found in a single individual among 800 Human Diversity Gene Panel samples.
Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families.
PMCID: PMC1764752  PMID: 17166276

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