Brain entropy and neurotrophic molecular markers accompanying clinical improvement after ketamine: Preliminary evidence in adolescents with treatment-resistant depression.

BACKGROUND: Current theory suggests that treatment-resistant depression (TRD) involves impaired neuroplasticity resulting in cognitive and neural rigidity, and that clinical improvement may require increasing brain flexibility and adaptability. AIMS: In this hypothesis-generating study, we sought to identify preliminary evidence of brain flexibility correlates of clinical change within the context of an open-label ketamine trial in adolescents with TRD, focusing on two promising candidate markers of neural flexibility: (a) entropy of resting-state functional magnetic resonance imaging (fMRI) signals; and (b) insulin-stimulated phosphorylation of mammalian target of rapamycin (mTOR) and glycogen synthase-3-beta (GSK3ß) in peripheral blood mononuclear cells. METHODS: We collected resting-state functional magnetic resonance imaging data and blood samples from 13 adolescents with TRD before and after a series of six ketamine infusions over 2 weeks. Usable pre/post ketamine data were available from 11 adolescents for imaging and from 10 adolescents for molecular signaling. We examined correlations between treatment response and changes in the central and peripheral flexibility markers. RESULTS: Depression reduction correlated with increased nucleus accumbens entropy. Follow-up analyses suggested that physiological changes were associated with treatment response. In contrast to treatment non-responders (n=6), responders (n=5) showed greater increase in nucleus accumbens entropy after ketamine, together with greater post-treatment insulin/mTOR/GSK3ß signaling. CONCLUSIONS: These data provide preliminary evidence that changes in neural flexibility may underlie symptom relief in adolescents with TRD following ketamine. Future research with adequately powered samples is needed to confirm resting-state entropy and insulin-stimulated mTOR and GSK3ß as brain flexibility markers and candidate targets for future clinical trials. CLINICAL TRIAL NAME: Ketamine in adolescents with treatment-resistant depressionURL: https://clinicaltrials.gov/ct2/show/NCT02078817Registration number: NCT02078817.

A randomized controlled trial of transcranial direct-current stimulation and cognitive training in children with fetal alcohol spectrum disorder.

BACKGROUND: This study was a randomized double-blind sham-controlled trial examining the effects of transcranial direct current stimulation (tDCS) augmented cognitive training (CT) in children with Fetal Alcohol Spectrum Disorders (FASD). Prenatal alcohol exposure has profound detrimental effects on brain development and individuals with FASD commonly present with deficits in executive functions including attention and working memory. The most commonly studied treatment for executive deficits is CT, which involves repeated drilling of exercises targeting the impaired functions. As currently implemented, CT requires many hours and the observed effect sizes are moderate. Neuromodulation via tDCS can enhance brain plasticity and prior studies demonstrate that combining tDCS with CT improves efficacy and functional outcomes. TDCS-augmented CT has not yet been tested in FASD, a condition in which there are known abnormalities in neuroplasticity and few interventions. METHODS: This study examined the feasibility and efficacy of this approach in 44 children with FASD. Participants were randomized to receive five sessions of CT with either active or sham tDCS targeting the dorsolateral prefrontal cortex, a region of the brain that is heavily involved in executive functioning. RESULTS: The intervention was feasible and well-tolerated in children with FASD. The tDCS group showed nominally significant improvement in attention on a continuous performance test compared to sham (p = .043). Group differences were observed at the third, fourth and fifth treatment sessions. There was no effect of tDCS on working memory (p = .911). Further, we found no group differences on a trail making task (p = .659) or on the verbal fluency test (p = .826). In the active tDCS group, a significant correlation was observed between improvement in attention scores and decrease in parent-reported attention deficits (p = .010). CONCLUSIONS: These results demonstrate that tDCS-augmented CT is well tolerated in children with FASD and potentially offers benefits over and above CT alone.

Deactivation in the posterior mid-cingulate cortex reflects perceptual transitions during binocular rivalry: Evidence from simultaneous EEG-fMRI.

Binocular rivalry is a phenomenon in which perception spontaneously shifts between two different images that are dichoptically presented to the viewer. By elucidating the cortical networks responsible for these stochastic fluctuations in perception, we can potentially learn much about the neural correlates of visual awareness. We obtained concurrent EEG-fMRI data for a group of 20 healthy human subjects during the continuous presentation of dichoptic visual stimuli. The two eyes' images were tagged with different temporal frequencies so that eye specific steady-state visual evoked potential (SSVEP) signals could be extracted from the EEG data for direct comparison with changes in fMRI BOLD activity associated with binocular rivalry. We additionally included a smooth replay condition that emulated the perceptual transitions experienced during binocular rivalry as a control stimulus. We evaluated a novel SSVEP-informed fMRI analysis in this study in order to delineate the temporal dynamics of rivalry-related BOLD activity from both an electrophysiological and behavioral perspective. In this manner, we assessed BOLD activity during rivalry that was directly correlated with peaks and crosses of the two rivaling, frequency-tagged SSVEP signals, for comparison with BOLD activity associated with subject reported perceptual transitions. Our findings point to a critical role of a right lateralized fronto-parietal network in the processing of bistable stimuli, given that BOLD activity in the right superior/inferior parietal lobules was significantly elevated throughout binocular rivalry and in particular during perceptual transitions, compared with the replay condition. Based on the SSVEP-informed analysis, rivalry was further associated with significantly enhanced BOLD suppression in the posterior mid-cingulate cortex during perceptual transitions, compared with SSVEP crosses. Overall, this work points to a careful interplay between early visual areas, the right posterior parietal cortex and the mid-cingulate cortex in mediating the spontaneous perceptual changes associated with binocular rivalry and has significant implications for future multimodal imaging studies of perception and awareness.

SSVEP signatures of binocular rivalry during simultaneous EEG and fMRI.

BACKGROUND: Binocular rivalry is a perceptual phenomenon that arises when two incompatible images are presented separately, one to each eye, and the observer experiences involuntary perceptual alternations between the two images. If the two images are flickering at two distinct frequencies, electroencephalography (EEG) can be used to track the frequency-tagged steady-state visually evoked potential (SSVEP) driven by each image as they compete for awareness, providing an objective measure of the subjective perceptual state. This spontaneous alternation in perceptual dominance is believed to be driven by neural processes across widespread regions in the brain, but the real-time mechanisms of these processes remain unclear. NEW METHOD: The goal of this study was to determine the feasibility of investigating binocular rivalry using a simultaneous EEG-fMRI approach in order to leverage the high temporal resolution of EEG with the high spatial resolution of fMRI. RESULTS: We have developed novel techniques for artifact removal and signal optimization for the rivalry-related SSVEP data collected simultaneously during fMRI. COMPARISON WITH EXISTING METHODS: Our methods address several significant technical challenges of recording SSVEP data in the noisy fMRI environment, and enabled us to successfully reconstruct SSVEP signatures of rivalry in a group of healthy human subjects. CONCLUSION: Further development and application of these techniques will enable more comprehensive integration of EEG and fMRI data collected simultaneously and could have significant implications for EEG-fMRI studies of brain activity in general.

High-definition transcranial direct current stimulation induces both acute and persistent changes in broadband cortical synchronization: a simultaneous tDCS-EEG study.

The goal of this study was to develop methods for simultaneously acquiring electrophysiological data during high-definition transcranial direct current stimulation (tDCS) using high-resolution electroencephalography (EEG). Previous studies have pointed to the after-effects of tDCS on both motor and cognitive performance, and there appears to be potential for using tDCS in a variety of clinical applications. However, little is known about the real-time effects of tDCS on rhythmic cortical activity in humans due to the technical challenges of simultaneously obtaining electrophysiological data during ongoing stimulation. Furthermore, the mechanisms of action of tDCS in humans are not well understood. We have conducted a simultaneous tDCS-EEG study in a group of healthy human subjects. Significant acute and persistent changes in spontaneous neural activity and event-related synchronization (ERS) were observed during and after the application of high-definition tDCS over the left sensorimotor cortex. Both anodal and cathodal stimulation resulted in acute global changes in broadband cortical activity which were significantly different than the changes observed in response to sham stimulation. For the group of eight subjects studied, broadband individual changes in spontaneous activity during stimulation were apparent both locally and globally. In addition, we found that high-definition tDCS of the left sensorimotor cortex can induce significant ipsilateral and contralateral changes in event-related desynchronization and ERS during motor imagination following the end of the stimulation period. Overall, our results demonstrate the feasibility of acquiring high-resolution EEG during high-definition tDCS and provide evidence that tDCS in humans directly modulates rhythmic cortical synchronization during and after its administration.

Simultaneous high-definition transcranial direct current stimulation of the motor cortex and motor imagery.

Transcranial direct current stimulation (tDCS) has been used to affect the excitability of neurons within the cerebral cortex. Improvements in motor learning have been found in multiple studies when tDCS was applied to the motor cortex during or before task learning is performed. The application of tDCS to motor imagery, a cognitive task showing activation in similar areas to motor execution, has resulted in differing effects based on the amplitude and duration of stimulation. We utilize high definition tDCS, a more spatially localized version of tDCS, to investigate the effect of anodal stimulation on human motor imagery performance. In parallel, we model this stimulation using a finite element model to calculate stimulation area and electrical field amplitude within the brain in the motor cortex and non-stimulated frontal and parietal regions. Overall, we found a delayed increase in resting baseline power 30 minutes post stimulation in both the right and left sensorimotor cortices which resulted in an increase in event-related desynchronization.

Neuromodulation for brain disorders: challenges and opportunities.

The field of neuromodulation encompasses a wide spectrum of interventional technologies that modify pathological activity within the nervous system to achieve a therapeutic effect. Therapies including deep brain stimulation, intracranial cortical stimulation, transcranial direct current stimulation, and transcranial magnetic stimulation have all shown promising results across a range of neurological and neuropsychiatric disorders. While the mechanisms of therapeutic action are invariably different among these approaches, there are several fundamental neuroengineering challenges that are commonly applicable to improving neuromodulation efficacy. This paper reviews the state-of-the-art of neuromodulation for brain disorders and discusses the challenges and opportunities available for clinicians and researchers interested in advancing neuromodulation therapies.

Evaluation of Density Functionals, SCC-DFTB, Neglect of Diatomic Differential Overlap (NDDO) Models and Molecular Mechanics Methods for Prolyl-Leucyl-Glycinamide (PLG) and Structural Derivatives.

Prolyl-leucyl-glycinamide (PLG) is a unique endogenous peptide that modulates dopamine receptor subtypes of the D(2) receptor family within the CNS. We seek to elucidate the structural basis and molecular mechanism by which PLG and its analogues modulate dopamine receptors, toward the development of new therapeutics to treat Parkinson's disease, tardive dyskinesia and schizophrenia. As a first step toward establishing a validated protocol for accurate computational modeling of PLG and associated peptidomimetic analogues, we evaluated the accuracy of density functional theory (DFT), wavefunction theory (WFT), and molecular mechanics (MM) calculations for PLG and for a library of structurally related small molecules. We first tested twelve local and nonlocal density functionals, Hartree-Fock (HF) theory, four "semiempirical" methods of the neglect of diatomic differential overlap (NDDO) type, and one self-consistent-charge nonorthogonal tight-binding (SCC-DFTB) method as implemented in two software suites, against coupled-cluster benchmark geometries for 4-methylthiazolidine, a small molecule that comprises key structural features present in our PLG analogue library. DFT and HF calculations were done with the MG3S augmented polarized triple-zeta basis set. We find that for 4-methylthiazolidine bond distances, DFT significantly outperforms NDDO, and both SCC-DFTB versions we evaluated perform worse than HF theory and are less accurate than 83% of the density functionals tested. The top five functionals for 4-methylthiazolidine were M05-2X, mPW1PW, B97-2, M06-2X, and PBEh, with mean unsigned errors (MUEs) in bond length of 0.0017, 0.0020, 0.0023, 0.0025 and 0.0027 Å, respectively. The widely used B3LYP functional ranked 11(th) out of twelve functionals evaluated, slightly below SCC-DFTB, and is significantly less accurate for 4-methylthiazolidine bond distances (MUE = 0.0095 Å) than the best local functional (M06-L, MUE = 0.0030 Å), which is far less computationally costly. Based on that initial analysis, we obtained new M05-2X benchmark geometric parameters for PLG and a library of eleven peptidomimetic derivatives, which we in turn used to examine the accuracy of thirty-four popular molecular mechanics (MM) force fields, four NDDO approaches, and SCC-DFTB for the full compound structures. Here, we found that ∼70% of the MM force fields tested superior to the best semiempirical and SCC-DFTB codings. Moreover, AMBER-type force fields proved most accurate among MM methods for this class of small-molecule peptidomimetics; the AMBER-type methods comprised eight out of the top ten molecular mechanics options we tested.