Rigor and reproducibility in research with transcranial electrical stimulation: An NIMH-sponsored workshop.

BACKGROUND: Neuropsychiatric disorders are a leading source of disability and require novel treatments that target mechanisms of disease. As such disorders are thought to result from aberrant neuronal circuit activity, neuromodulation approaches are of increasing interest given their potential for manipulating circuits directly. Low intensity transcranial electrical stimulation (tES) with direct currents (transcranial direct current stimulation, tDCS) or alternating currents (transcranial alternating current stimulation, tACS) represent novel, safe, well-tolerated, and relatively inexpensive putative treatment modalities. OBJECTIVE: This report seeks to promote the science, technology and effective clinical applications of these modalities, identify research challenges, and suggest approaches for addressing these needs in order to achieve rigorous, reproducible findings that can advance clinical treatment. METHODS: The National Institute of Mental Health (NIMH) convened a workshop in September 2016 that brought together experts in basic and human neuroscience, electrical stimulation biophysics and devices, and clinical trial methods to examine the physiological mechanisms underlying tDCS/tACS, technologies and technical strategies for optimizing stimulation protocols, and the state of the science with respect to therapeutic applications and trial designs. RESULTS: Advances in understanding mechanisms, methodological and technological improvements (e.g., electronics, computational models to facilitate proper dosing), and improved clinical trial designs are poised to advance rigorous, reproducible therapeutic applications of these techniques. A number of challenges were identified and meeting participants made recommendations made to address them. CONCLUSIONS: These recommendations align with requirements in NIMH funding opportunity announcements to, among other needs, define dosimetry, demonstrate dose/response relationships, implement rigorous blinded trial designs, employ computational modeling, and demonstrate target engagement when testing stimulation-based interventions for the treatment of mental disorders.

Rethinking mental disorders: the role of learning and brain plasticity.

Recent research in neurodevelopment, neuroplasticity and genetics is providing new insights into the etiogenesis of psychopathology, but progress in treatment development has been hampered by reliance on diagnostic categories that are characterized by heterogeneity and based primarily on phenomenology. The NIMH Research Domain Criteria (RDoC) initiative seeks to provide a neuroscience-based nosological framework for future research on psychopathology, categorizing individuals for research purposes using a dimensional approach that capitalizes on advances in modern neuroscience. These scientific advances and new approaches to classification can inform the development of novel, circuit-based interventions and the personalization of treatment. In this paper, we review key advances areas in clinical neuroscience, describe the RDoC project and highlight some emerging treatment approaches that are consistent with these developments.

Harnessing neuroplasticity for clinical applications.

Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.

Corpus Callosum Shape Analysis with Application to Dyslexia.

Morphometric studies of the corpus callosum suggest its involvement in a number of psychiatric conditions. In the present study we introduce a novel pattern recognition technique that offers a point-by-point shape descriptor of the corpus callosum. The method uses arc lengths of electric field lines in order to avoid discontinuities caused by folding anatomical contours. We tested this technique by comparing the shape of the corpus callosum in a series of dyslexic men (n = 16) and age-matched controls (n = 14). The results indicate a generalized increase in size of the corpus callosum in dyslexia with a concomitant diminution at its rostral and caudal poles. The reported shape analysis and 2D-reconstruction provide information of anatomical importance that would otherwise passed unnoticed when analyzing size information alone.

Increased white matter gyral depth in dyslexia: implications for corticocortical connectivity.

Recent studies provide credence to the minicolumnar origin of several developmental conditions, including dyslexia. Characteristics of minicolumnopathies include abnormalities in how the cortex expands and folds. This study examines the depth of the gyral white matter measured in an MRI series of 15 dyslexic adult men and eleven age-matched comparison subjects. Measurements were based upon the 3D Euclidean distance map inside the segmented cerebral white matter surface. Mean gyral white matter depth was 3.05 mm (SD +/- 0.30 mm) in dyslexic subjects and 1.63 mm (SD +/- 0.15 mm) in the controls. The results add credence to the growing literature suggesting that the attained reading circuit in dyslexia is abnormal because it is inefficient. Otherwise the anatomical substratum (i.e., corticocortical connectivity) underlying this inefficient circuit is normal. A deficit in very short-range connectivity (e.g., angular gyrus, striate cortex), consistent with results of a larger gyral window, could help explain reading difficulties in patients with dyslexia. The structural findings hereby reported are diametrically opposed to those reported for autism.

Reduced gyral window and corpus callosum size in autism: possible macroscopic correlates of a minicolumnopathy.

Minicolumnar changes that generalize throughout a significant portion of the cortex have macroscopic structural correlates that may be visualized with modern structural neuroimaging techniques. In magnetic resonance images (MRIs) of fourteen autistic patients and 28 controls, the present study found macroscopic morphological correlates to recent neuropathological findings suggesting a minicolumnopathy in autism. Autistic patients manifested a significant reduction in the aperture for afferent/efferent cortical connections, i.e., gyral window. Furthermore, the size of the gyral window directly correlated to the size of the corpus callosum. A reduced gyral window constrains the possible size of projection fibers and biases connectivity towards shorter corticocortical fibers at the expense of longer association/commisural fibers. The findings may help explain abnormalities in motor skill development, differences in postnatal brain growth, and the regression of acquired functions observed in some autistic patients.

Magnetic resonance imaging study of brain asymmetries in dyslexic patients.

Research studies suggest that the left hemisphere is involved in the pathophysiology of dyslexia. Thus far, the exact location and nature of the purported lesion(s) remain a matter of contention. The present study describes the distribution of structural abnormalities as related to brain symmetry in the brains of dyslexic individuals. High-resolution three-dimensional magnetic resonance images (MRIs) were analyzed in 16 dyslexic men and 14 controls matched for sex, age, educational level, and handedness. A computerized image analysis system was used to assess the volumetric deformations required to match each brain with its left-right mirror image. The results showed significant abnormalities in five left hemisphere structures involving the extrapyramidal and limbic systems: amygdala, hippocampus proper, parahippocampal gyrus, putamen, and globus pallidus. The left hemisphere is thought to play a major role in the temporal analysis of information. This stream of temporal analysis is of importance in motor movements. Reading might have evolved as an exaptation to motor movements requiring the sequential analysis of information.

Reduced brain size and gyrification in the brains of dyslexic patients.

Dyslexia is a specific learning disability that affects the way in which a person acquires reading skills. The pathologic substrate of the condition has been debated in the literature. Conclusions from postmortem studies remain controversial because series have been based on few and often ill-characterized cases. The present article expands on one of the reported neuropathologic findings in dyslexia, that is, wider minicolumns. Measurements were made of magnetic resonance images in a series of 16 dyslexic and 14 age- and sex-matched controls. Dyslexic patients had significantly smaller total cerebral volume (P = .014) and reduced gyrification index (P = .021). No changes were noted in cortical thickness, the ratio of gray to white matter, or the cross-sectional areas of the corpus callosum and medulla oblongata. The findings, although not conclusive, are in keeping with a minicolumnar defect in dyslexia. The decreased gyrification and preserved cortical thickness can alter the information processing capacity of the brain by providing a greater degree of cortical integration at the expense of a slower response time. The article also emphasizes the contrast between findings in dyslexia and in autism.