Safety of focused ultrasound neuromodulation in humans with temporal lobe epilepsy.

OBJECTIVE: Transcranial Focused Ultrasound (tFUS) is a promising new potential neuromodulation tool. However, the safety of tFUS neuromodulation has not yet been assessed adequately. Patients with refractory temporal lobe epilepsy electing to undergo an anterior temporal lobe resection present a unique opportunity to evaluate the safety and efficacy of tFUS neuromodulation. Histological changes in tissue after tFUS can be examined after surgical resection, while further potential safety concerns can be assessed using neuropsychological testing. METHODS: Neuropsychological functions were assessed in eight patients before and after focused ultrasound sonication of the temporal lobe at intensities up to 5760 mW/cm2. Using the BrainSonix Pulsar 1002, tFUS was delivered under MR guidance, using the Siemens Magnetom 3T Prisma scanner. Neuropsychological changes were assessed using various batteries. Histological changes were assessed using hematoxylin and eosin staining, among others. RESULTS: With respect to safety, the histological analysis did not reveal any detectable damage to the tissue, except for one subject for whom the histology findings were inconclusive. In addition, neuropsychological testing did not show any statistically significant changes in any test, except for a slight decrease in performance on one of the tests after tFUS. SIGNIFICANCE: This study supports the hypothesis that low-intensity Transcranial Focused Ultrasound (tFUS) used for neuromodulation of brain circuits at intensities up to 5760 mW/cm2 may be safe for use in human research. However, due to methodological limitations in this study and inconclusive findings, more work is warranted to establish the safety. Future directions include greater number of sonications as well as longer exposure at higher intensity levels to further assess the safety of tFUS for modulation of neuronal circuits.

Design, Development, and Operation of a Low-Intensity Focused Ultrasound Pulsation (LIFUP) System for Clinical Use.

Noninvasive low-intensity focused ultrasound pulsation (LIFUP) neuromodulation provides a unique approach to both investigating and treating the brain. This work describes a well-calibrated, simple-to-use ultrasound stimulation system for neuromodulation studies. It provides a single-element 650-kHz transducer design and a straightforward control mechanism, with extensive calibration and internal electronic monitoring to prevent unwanted over or under treatment. One goal of this approach is to relieve researchers of many of the details associated with developing their own exposure equipment. A unique transducer positioning system and distinctive MRI fiducial targets simplify alignment and targeting. The system design, control software, calibration, and alignment techniques are described in detail. Examples of transducer targeting and neurostimulation using the system are provided.

Bringing Neuroscience to the Bedside.

Clinical psychiatry has not historically expected practitioners to learn the basic science of psychiatric illness. Despite wide recognition that all effective psychiatric treatments have neurophysiological mechanisms, the field has struggled to integrate concepts of the mind and brain. Because of historical separations of clinical psychiatry and evolving neuroscience research, many psychiatric residency programs feel underresourced to teach clinically relevant neuroscience, and current residency graduates are not being prepared to integrate neuroscience findings into their practice. Significant strides have been made in the understanding of the neurobiology of psychiatric disorders. Similarly, the neurobiological mechanisms of a wide variety of treatments have been elucidated, spanning interventions from psychotherapy to physical exercise, electroconvulsive therapy, and modern neuromodulation techniques. The authors discuss strategies for integrating the language of clinical neuroscience into everyday psychiatric practice and review resources available to clinicians and trainees to help them acquire and practice these skills.

Neurophysiologic predictors of response to atomoxetine in young adults with attention deficit hyperactivity disorder: a pilot project.

Atomoxetine is a non-stimulant medication with sustained benefit throughout the day, and is a useful pharmacologic treatment option for young adults with Attention-Deficit/Hyperactivity Disorder (ADHD). It is difficult to determine, however, those patients for whom atomoxetine will be both effective and advantageous. Patients may need to take the medication for several weeks before therapeutic benefit is apparent, so a biomarker that could predict atomoxetine effectiveness early in the course of treatment could be clinically useful. There has been increased interest in the study of thalamocortical oscillatory activity using quantitative electroencephalography (qEEG) as a biomarker in ADHD. In this study, we investigated qEEG absolute power, relative power, and cordance, which have been shown to predict response to reuptake inhibitor antidepressants in Major Depressive Disorder (MDD), as potential predictors of response to atomoxetine. Forty-four young adults with ADHD (ages 18-30) enrolled in a multi-site, double-blind placebo-controlled study of the effectiveness of atomoxetine and underwent serial qEEG recordings at pretreatment baseline and one week after the start of medication. qEEG measures were calculated from a subset of the sample (N = 29) that provided useable qEEG recordings. Left temporoparietal cordance in the theta frequency band after one week of treatment was associated with ADHD symptom improvement and quality of life measured at 12 weeks in atomoxetine-treated subjects, but not in those treated with placebo. Neither absolute nor relative power measures selectively predicted improvement in medication-treated subjects. Measuring theta cordance after one week of treatment could be useful in predicting atomoxetine treatment response in adult ADHD.

Do prefrontal midline electrodes provide unique neurophysiologic information in Major Depressive Disorder?

Brain oscillatory activity from the midline prefrontal region has been shown to reflect brain dysfunction in subjects with Major Depressive Disorder (MDD). It is not known, however, whether electrodes from this area provide unique information about brain function in MDD. We examined a set of midline sites and two other prefrontal locations for detecting cerebral activity differences between subjects with MDD and healthy controls. Resting awake quantitative EEG (qEEG) data were recorded from 168 subjects: 47 never-depressed adults and 121 with a current major depressive episode. Individual midline electrodes (Fpz, Fz, Cz, Pz, and Oz) and prefrontal electrodes outside the hairline (Fp1, Fp2) were examined with absolute and relative power and cordance in the theta band. We found that MDD subjects exhibited higher values of cordance (p = 0.0066) at Fpz than controls; no significant differences were found at other locations, and power measures showed trend-level differences. Depressed adults showed higher midline cordance than did never-depressed subjects at the most-anterior midline channel. Salient abnormalities in MDD may be detectable by focusing on the prefrontal midline region, and EEG metrics from focused electrode arrays may offer clinical practicality for clinical monitoring.

Low-intensity focused ultrasound pulsation device used during magnetic resonance imaging: evaluation of magnetic resonance imaging-related heating at 3 Tesla/128 MHz.

OBJECTIVE: The objective of this study was to determine magnetic resonance imaging (MRI)-related heating for a low-intensity focused ultrasound pulsation (LIFUP) device used during MRI performed at 3 T/128 MHz. MATERIALS AND METHODS: A special phantom was constructed to mimic the thermal properties of the human brain, and a piece of human temporal bone (skull) was embedded on top. Four fluoroptic thermometry probes, placed above and below the skull, were used to measure temperature changes during MRI (3 T/128 MHz; scanner-reported head average specific absorption rate 1.1-2 W/kg) with and without concurrent LIFUP sonication. LIFUP sonication was applied using a focused ultrasound device (BXPulsar 1001, Brainsonix, Inc., Los Angeles, CA, USA) at a derated spatial-peak temporal-average intensity of 3870 mW/cm(2) . RESULTS: MRI performed at relatively high specific absorption rate (SAR) caused a slight elevation in temperature (≤0.6°C). Concurrent use of MRI at a medium-strength SAR and LIFUP sonication resulted in maximum temperature rise of 3.1°C after 8 min of continuous use. CONCLUSIONS: Under the specific conditions utilized for this investigation, LIFUP sonication does not appear to present significant heating risks when used concurrently with MRI. This information has important implications for the use of the LIFUP sonication in human subjects undergoing MRI at 3 T/128 MHz.

Rostral anterior cingulate activity in major depressive disorder: state or trait marker of responsiveness to medication?

High rostral anterior cingulate cortex (rACC) activity has been shown to predict antidepressant treatment response; however, it is unclear whether this is a fixed versus variable marker of responsiveness. The authors measured rACC theta current density in 22 subjects 5 weeks before and again immediately before 5 weeks of blinded treatment with sertraline. Mixed-effects regression analysis found that the relationship between response and rACC activity depended significantly on the timing of the rACC assessment; rACC activity measured immediately before treatment was a significantly better predictor of response. rACC activity may constitute a variable "state" indicator of responsiveness to antidepressants.

Rostral anterior cingulate cortex activity and early symptom improvement during treatment for major depressive disorder.

In treatment trials for major depressive disorder (MDD), early symptom improvement is predictive of eventual clinical response. Clinical response may also be predicted by elevated pretreatment theta (4-7Hz) current density in the rostral anterior cingulate (rACC) and medial orbitofrontal cortex (mOFC). We investigated the relationship between pretreatment EEG and early improvement in predicting clinical outcome in 72 MDD subjects across three placebo-controlled treatment trials. Subjects were randomized to receive fluoxetine, venlafaxine, or placebo. Theta current density in the rACC and mOFC was computed with Low-Resolution Brain Electromagnetic Tomography (LORETA). An analysis of covariance examining week-8 Hamilton Depression Rating Scale (HamD) percent change, showed a significant effect of week-2HamD percent change, and a significant three-way interaction of week-2HamD percent change×treatment×rACC. Medication subjects with robust early improvement showed almost no relationship between rACC theta current density and final clinical outcome. However, in subjects with little early improvement, rACC activity showed a strong relationship with clinical outcome. The model examining the mOFC showed a trend in the three-way interaction. A combination of pretreatment rACC activity and early symptom improvement may be useful for predicting treatment response.

Amygdala lateralization at rest and during viewing of neutral faces in major depressive disorder using low-resolution brain electromagnetic tomography.

Neuroimaging experiments of amygdala activity during rest have shown abnormal amygdalar lateralization in Major Depressive Disorder (MDD). The current study is an exploratory investigation of the use of the neuroimaging technique Low Resolution Electromagnetic Tomography (LORETA) to measure current source density (CSD) in the amygdala. We examined seven adults with MDD and nine healthy control subjects at rest, and while they viewed images of emotionally neutral faces. The primary purpose was to compare the findings of LORETA with published findings using other neuroimaging techniques. Four frequency bands were examined: delta (1-3 Hz), theta (3-7 Hz), alpha (7-11 Hz), and beta (11-29 Hz). Results showed that for both MDD and control groups, the right amygdala displayed higher overall activity (across frequencies) than the left, both at rest, and while viewing neutral faces. Results also showed that controls displayed significant differences between resting and viewing neutral images across all four bands in the right amygdala, with all four bands having higher CSD values in the right amygdala. There were no significant differences in CSD values between rest vs. viewing neutral images in the MDD group. Findings suggest a more pronounced lateralization effect in normal healthy controls than in MDD subjects when changing from a resting (eyes-closed) condition to viewing faces without emotional valence.

Functional neuroanatomy of visual masking deficits in schizophrenia.

CONTEXT: Visual masking procedures assess the earliest stages of visual processing. Patients with schizophrenia reliably show deficits on visual masking, and these procedures have been used to explore vulnerability to schizophrenia, probe underlying neural circuits, and help explain functional outcome. OBJECTIVE: To identify and compare regional brain activity associated with one form of visual masking (ie, backward masking) in schizophrenic patients and healthy controls. DESIGN: Subjects received functional magnetic resonance imaging scans. While in the scanner, subjects performed a backward masking task and were given 3 functional localizer activation scans to identify early visual processing regions of interest (ROIs). SETTING: University of California, Los Angeles, and the Department of Veterans Affairs Greater Los Angeles Healthcare System. PARTICIPANTS: Nineteen patients with schizophrenia and 19 healthy control subjects. Main Outcome Measure The magnitude of the functional magnetic resonance imaging signal during backward masking. RESULTS: Two ROIs (lateral occipital complex [LO] and the human motion selective cortex [hMT+]) showed sensitivity to the effects of masking, meaning that signal in these areas increased as the target became more visible. Patients had lower activation than controls in LO across all levels of visibility but did not differ in other visual processing ROIs. Using whole-brain analyses, we also identified areas outside the ROIs that were sensitive to masking effects (including bilateral inferior parietal lobe and thalamus), but groups did not differ in signal magnitude in these areas. CONCLUSIONS: The study results support a key role in LO for visual masking, consistent with previous studies in healthy controls. The current results indicate that patients fail to activate LO to the same extent as controls during visual processing regardless of stimulus visibility, suggesting a neural basis for the visual masking deficit, and possibly other visual integration deficits, in schizophrenia.

Rostral anterior cingulate cortex theta current density and response to antidepressants and placebo in major depression.

OBJECTIVE: To assess whether pretreatment theta current density in the rostral anterior cingulate (rACC) and medial orbitofrontal cortex (mOFC) differentiates responders from non-responders to antidepressant medication or placebo in a double-blinded study. METHODS: Pretreatment EEGs were collected from 72 subjects with Major Depressive Disorder (MDD) who participated in one of three placebo-controlled trials. Subjects were randomized to receive treatment with fluoxetine, venlafaxine, or placebo. Low-resolution brain electromagnetic tomography (LORETA) was used to assess theta current density in the rACC and mOFC. RESULTS: Medication responders showed elevated rACC and mOFC theta current density compared to medication non-responders (rACC: p=0.042; mOFC: p=0.039). There was no significant difference in either brain region between placebo responders and placebo non-responders. CONCLUSIONS: Theta current density in the rACC and mOFC may be useful as a biomarker for prediction of response to antidepressant medication. SIGNIFICANCE: This is the first double-blinded treatment study to examine pretreatment rACC and mOFC theta current density in relation to antidepressant response and placebo response. Results support the potential clinical utility of this approach for predicting clinical outcome to antidepressant treatments in MDD.

A new paradigm for the prediction of antidepressant treatment response.

Current treatment of Major Depressive Disorder utilizes a trial-and-error sequential treatment strategy that results in delays in achieving response and remission for a majority of patients. Protracted ineffective treatment prolongs patient suffering and increases health care costs. In addition, long and unsuccessful antidepressant trials may diminish patient expectations, reinforce negative cognitions, and condition patients not to respond during subsequent antidepressant trials, thus contributing to further treatment resistance. For these reasons, it is critical to identify reliable predictors of antidepressant treatment response that can be used to shorten or eliminate lengthy and ineffective trials. Research on possible endophenotypic as well as genomic predictors has not yet yielded reliable predictors. The most reliable predictors identified thus far are symptomatic and physiologic characteristics of patients that emerge early in the course of treatment. We propose here the term "response endophenotypes" (REs) to describe this class of predictors, defined as latent measurable symptomatic or neurobiologic responses of individual patients that emerge early in the course of treatment, and which carry strong predictive power for individual patient outcomes. Use of REs constitutes a new paradigm in which medication treatment trials that are likely to be ineffective could be stopped within 1 to 2 weeks and other medication more likely to be effective could be started. Data presented here suggest that early changes in symptoms, quantitative electroencephalography, and gene expression could be used to construct effective REs. We posit that this new paradigm could lead to earlier recovery from depressive illness and ultimately produce profound health and economic benefits.

Brain electrical source differences between depressed subjects and healthy controls.

Many brain regions show metabolic and perfusion abnormalities in major depressive disorder (MDD), including anterior cingulate and prefrontal cortices. Some of these same areas also show abnormal function with low resolution electromagnetic tomography (LORETA). However, LORETA results are not always consistent across studies, nor with findings from other imaging modalities. These discrepancies may be due, among other factors, to the sensitivity of EEG source localization to different electrode montages. Thirty-six channel EEG was collected from healthy controls and age- and gender-matched unmedicated subjects with MDD (n = 74). EEGs were analyzed with LORETA to assess resting state current density at each of 2,394 cortical voxels. For comparison to previous studies, LORETA was performed using all electrodes or with specific prefrontal electrodes removed. Voxel-by-voxel differences between the depressed and healthy groups were calculated using non-parametric statistics. MDD subjects showed significantly elevated current density in delta, theta, alpha, beta1, and beta2 frequency bands relative to controls in anterior cingulate and prefrontal cortices. Removal of certain prefrontal electrodes from input to LORETA decreased or eliminated significant differences between groups. LORETA detects differences in brain activity between MDD subjects and healthy controls that are consistent with previous findings using other imaging modalities. Inconsistent findings among LORETA studies, and between LORETA studies and those using other functional imaging techniques, may result from differences in electrode montages.