Abstracts / Brain Stimulation 10 (2017) 346e540
 PROCEDURAL PSYCHIATRY e A NEW KIND OF PSYCHIATRY THAT USES MACHINES
 NON-INVASIVE BRAIN STIMULATION e A MODERN APPROACH TO IMPROVED THERAPY OF ANXIETY DISORDERS?
R. Berlow*. ABSC, USA
A.J. Fallgatter*. University of Tuebingen, Germany
Background: With so many new diagnostic and therapeutic procedures available in psychiatry a new conceptual framework may be needed. Psychiatrists who treat (patients not in remission) have a duty to know and make known these options. When medications/therapy does not produce remission, there are advanced options. Results: Diagnostic Procedures: EEG in the diagnosis of ADHD in children age 6-17 was the ﬁrst biological FDA cleared test in psychiatry(2013). Primary ADHD often has a higher Theta/Beta ratio as opposed to secondary attentional problems. Genetic testing for SNPs involving genes for neurotransmitter receptors and liver metabolism genes is ﬁnding increased use. Heart rate variability is a marker of severity, TRD refractory depression may uncover markers of pathology in folate metabolism or the serotonin. Therapeutic Procedures: Transcranial Magnetic Stimulation was FDA cleared for depression in 2008. Since then 5 advanced options have emerged. Theta Burst Stimulation uses a 50Hz/5Hz combination, offering increased efﬁciency (6 vs 37.5 minutes) and the option of inhibition (continuous TBS). Deep Coil TMS is standard in one system, and off label in two other systems. Peak alpha frequency stimulation has been used in schizophrenia and major depression. Neuronavigation has been used for depression at L-DLPFC, or R-DLPFC, with TBS and for suicidality. Electric: CES has been available and approved for more than 20 years. A trigeminal nerve stimulation device for headache was FDA cleared (2104) and also used for anxiety, depression and PTSD. Transcutaneous vagus nerve stimulation devices are available in Europe for headache and seizures. Transcranial direct current Stimulation has been the subject of remarkable research but has seen little use in the clinic. Conclusions: More psychiatrists in practice are using procedures and a subspecialty may emerge. Declarative and Procedural Psychiatry are not mutually exclusive, but can be integrated for the beneﬁt of patients. Keywords: Procedural Psychiatry, Current Options, Outpatient Treatment
Anxiety disorders are the most frequent psychiatric disorders worldwide. The most severe form is panic disorder with a very unfavourable spontaneous course. Although state-of-the art treatment with cognitive behavioural therapy, pharmacotherapy or a combination of both is effective, roughly one third of patients can not be treated sufﬁciently. In the past years, several attempts have been made to improve standard treatment of panic disorders by means of non-invasive brain stimulation, in particular Transcranial Magnetic Stimulation (rTMS) to the prefrontal cortex. In a pilot study, we investigated whether 15 sessions of intermittent Theta Burst Stimulation (iTBS) to the left dorsolateral prefrontal cortex applied as add-on treatment to cognitive behavioral therapy might have a beneﬁcial therapeutic effect. Patients with panic disorder (n ¼ 44) were randomly assigned to verum or sham stimulation groups. Although we did not ﬁnd signiﬁcantly different reduction in anxiety symptoms, exploratory analyses pointed to a possible beneﬁcial effect (reduction of medication during the treatment phase only in the verum stimulation group). Neurophysiological effects as assessed with Near-Infrared Spectroscopy (NIRS) in terms of a normalized function of the lateral prefrontal cortex during emotional paradigms were found only in the verum stimulated patients. In conclusion, we provide hints for a beneﬁcial effect of additional iTBS in the treatment of patients with panic disorders mainly on the neurophysiological and, to a lesser extent, on the clinical level. Keywords: TMS, anxiety, treatment
 MESOSCALE CORTICAL MAPPING REVEALS REGION-SPECIFIC AND FREQUENCY-DEPENDENT CHANGES IN A MOUSE MODEL OF ELECTROCONVULSIVE THERAPY D.B. Jovellar*, J. LeDue, T.H. Murphy. University of British Columbia, Canada Introduction: Depression is a leading cause of disability worldwide. As a treatment for depression, electroconvulsive therapy (ECT) remains the most effective. In spite of such unparalleled efﬁcacy, our understanding of the therapeutic mechanisms of ECT remains lacking. Using Electroconvulsive stimulation (ECS)dan animal model of ECTdwe determine how ECT alters the mesoscale spatiotemporal activity of different brain regions. Methods: Wide-ﬁeld ﬂuorescent imaging of resting-state activity was performed in awake head-ﬁxed mice expressing GCaMP6 (a geneticallyencoded calcium indicator). This allowed longitudinal imaging of intracellular calcium which reﬂect changes in spiking activity at a cellular level. ECS was done once daily, every other day, for a total of 10 treatments. Imaging was done daily ~10 min and 24h after ECS. Results: Quantiﬁcation of GCaMP6 ﬂuorescence revealed increased standard deviation of spontaneous activity in the anterior cingulate. This parallels the increased amplitude of low-frequency ﬂuctuations (ALFFs), which is a measure of regional brain activity, in some fMRI studies. An even greater increase in standard deviation of resting-state activity was observed in the restrosplenial cortex. Further analyses demonstrated increased power of the retrosplenial cortex at the delta frequency band (14 Hz). Conclusion: These ﬁndings suggest that ECS effects are brain-region speciﬁc and are frequency-dependent. To our knowledge, this is the ﬁrst animal model that incorporates longitudinal imaging of spiking activity after ECS and provides opportunities to further dissect the therapeutic mechanism of ECT. Keywords: Electroconvulsive stimulation, Electroconvulsive therapy, depression, calcium imaging
 IMPROVING LOWER LIMB STRENGTH IN INCOMPLETE SPINAL CORD INJURY WITH NON-INVASIVE SPINAL ASSOCIATIVE STIMULATION M. Cortes*1, 2, G. Thickbroom 3, J. Valls-Sole 2, P. Shirvalkar 1, A. PascualLeone 4, D. Edwards 1, 3. 1 Cornell University, USA; 2 Barcelona University, Spain; 3 University of Western Australia, Australia; 4 Harvard medical school, USA Introduction: The corticospinal pathway is an important target for motor recovery after spinal cord injury (SCI) in humans. In healthy controls the excitability of this pathway can be increased at the spinal level by repeatedly delivering central and peripheral stimulus pairs that are timed so that the volleys arrive coincide at the corticospinal motorneuronal (MTN) synapses of lower extremity (spinal associative stimulation, SAS). In the present study, we hypothesize that SAS could increase excitability of the corticospinal pathway in chronic incomplete SCI (iSCI) and that this could increase voluntary motor output. Objective: (1) Conﬁrm that the SAS pairing interval could indeed alter Hreﬂex threshold and form a rational basis for repetitive application, and (2) sufﬁciently modulate corticospinal pathways to augment spinal responsiveness of descending volitional drive post-intervention. Methods: 11 people with chronic incomplete SCI and some degree of motor dysfunction in the soleus muscle were included in the study. Each participant received one SAS session, which involves 15 minutes of paired subthreshold TMS delivered 20ms prior a peripheral stimulation in the posterior tibial nerve, repeated at 0.1Hz (90 stimuli pairs). Outcome measures (H-reﬂex threshold and amplitude, soleus muscle maximum voluntary contraction, soleus MEP) were determined at baseline and post-intervention Results: In 11 iSCI subjects the H-reﬂex amplitude signiﬁcantly increased when conditioned by a descending volley from motor cortex (conditionedH pre 0.102mV±0.04; post 0.555±0.15; p¼0.001; mean±SEM). Following SAS there was an increase in voluntary MVC from the soleus muscle (pre 0.028±0.0051; post 0.032±0.0064; p¼0.03; mean±SEM), but not in the TA muscle (results). Conclusions: SAS can increase voluntary motor output to a target muscle after iSCI, and the effect is speciﬁc to that muscle. Modulation of the corticospinal-motorneuron synapses has the potential to be a promising adjunct to rehabilitation therapy for enhancing voluntary motor output in disorders affecting the corticospinal tract.
Abstracts / Brain Stimulation 10 (2017) 346e540
Keywords: transcranial magnetic stimulation, spinal cord injury, motor recovery, H-reﬂex  METHODS TO EXAMINE I-WAVE INTERACTIONS AND EFFECTS OF AFFERENT INPUT R. Chen*. University of Toronto, Canada A single transcranial magnetic stimulation (TMS) pulse to the motor cortex evoked a series of corticospinal volleys known as direct (D) and indirect (I) waves. This talk will discuss methods to assess D and I waves, how they are altered by afferent input and potential clinical implications. TMS with induced current in the posterior-anterior (PA) direction preferentially evokes early (I1) wave whereas anterior-posterior (AP) TMS preferentially evokes late (I3) waves. The interaction between I-waves can be studied with a paired pulse TMS paradigm known as short-interval intracortical facilitation (SICF), with peak facilitations at ~ 1.5, 3.0 and 4.5 ms that correspond to interactions between different I-waves. Afferent input, such as median nerve stimulation, inhibits the motor cortex at about 20 ms, known as short-latency afferent inhibition (SAI). SAI is mediated by acetylcholine and GABA, is altered in Alzheimer’s and Parkinson’s disease and predominately inhibit late I-waves evoked in the PA direction. Unexpectedly, it was found that SAI was greater with TMS in the PA compared to the AP direction. Single motor unit poststimulus time histogram recordings conﬁrmed that the AP TMS preferentially evoked late I-waves, and late I-waves from PA TMS were inhibited by SAI whereas late I-waves from AP TMS were not. These ﬁndings suggest that late I-waves generated by AP and PA current are mediated by different circuits. The interactions between SAI and SICF were also investigated. Contrary to expectation, SICF elicited by both AP and PA current directions was facilitated in the presence of SAI. These results are compatible with the ﬁnding that projections from sensory to motor cortex terminate in both superﬁcial layers where late I-waves are thought to originate, as well as deeper layers with more direct effect on pyramidal output. This interaction is likely to be relevant to sensorimotor integration and motor control.  I-WAVE INTERACTIONS FOLLOWING HUMAN SPINAL CORD INJURY M.A. Perez*. University of Miami, USA The effect of a CNS injury on methodologies used to assess (D) and indirect (I) waves by using transcranial magnetic stimulation (TMS) of the human motor cortex remain poorly understood. Here, I will discuss the effect of an incomplete cervical spinal cord injury (SCI) on these methodologies. Paired-pulse TMS results in consecutive facilitatory motor evoked potential peaks in surface electromyography that resemble activation of early and late I-waves. We found that after SCI late I-waves aberrantly contributed to spinal motoneuron recruitment. We argue that the later corticospinal inputs on the spinal cord might be crucial for recruitment of motoneurones after human SCI. We have also used coil rotations to examine cortico-cortical contribution to grasping behaviours in humans with and without incomplete SCI. The TMS coil was oriented to induce currents in the brain in the latero-medial (LM), posterior-anterior (PA), and anterior-posterior (AP) direction to preferentially activate corticospinal axons directly and early and late synaptic inputs to corticospinal neurons, respectively. AP-LM MEP latency differences were consistently longer during power grip compared with index ﬁnger abduction and precision grip, while PA-LM differences remained similar across tasks. Note that these latency differences across tasks were decreased in humans with SCI. A preferential recruitment of late synaptic inputs to corticospinal neurons may be achieved when humans perform a power grip. This information may contribute to the design of future interventions using TMS following SCI and other motor disorders affecting the corticospinal tract.  COMPUTATIONAL MODELLING OF CORTICAL TRANSCRANIAL MAGNETIC STIMULATION J. Triesch*. JW. Goethe University, Germany
Transcranial magnetic stimulation (TMS) holds great promise for various clinical and basic research applications. Despite decades of research, however, the precise mechanisms through which TMS induces activity in cortical and peripheral structures are still insufﬁciently understood. Computational models can help to explore putative underlying mechanisms and test their plausibility and consistency. Over the last years, we have been developing and reﬁning such a model, which offers a parsimonious explanation of the mechanisms generating so-called D and I-waves. The model has a simple structure comprising excitatory and inhibitory neurons in cortical layers two and three that project to a population of corticospinal tract neurons in layer ﬁve. The model correctly captures the basic ﬁndings about D and I-waves and how they are affected by pharmacological interventions. The model also explains the effects of a number of paired-pulse stimulation protocols. More recently, we have extended the model to simulate how TMS over motor cortex drives activity in down-stream motor structures. Our model produces realistic motor evoked potentials (MEPs) and shows how their magnitude is affected by stimulation intensity and the level of voluntary muscle contraction. The model also produces cortical silence periods (CSPs) of realistic lengths and reveals how their duration depends on properties of intra-cortical inhibition. Finally, the model shows how cortical rhythms such as the prominent mu-rhythm of motor cortex contribute to the variability of neural responses to TMS, consistent with the observation that TMS triggered at different phases of the mu-rhythm produces systematically different response magnitudes. Overall, the proposed computational model offers a parsimonious account of the basic effects of TMS on cortical circuits. In the future, this could be exploited for optimizing stimulation protocols for speciﬁc clinical or basic research applications.  EPIDURAL ACTIVITY EVOKED BY DIFFERENT FORMS OF BRAIN STIMULATION v. Di Lazzaro*. Policlinico Universitario Campus Bio-Medico, Italy The activity evoked by transcranial electric (TES) and magnetic (TMS) stimulation of the human brain can be visualised directly in patients who have had electrodes’ implanted surgically in the epidural space of the cervical cord for control of pain. The recordings in these patients have shown that a single stimulus to motor cortex evokes a synchronised series of descending activity very similar to those recorded in primates after direct stimulation of the cortical surface. At threshold for producing a muscle contraction, TES evokes a single rapidly conducted volley at short latency that by analogy to the primate data is termed the “D-wave” because it is caused by direct excitation of the axons of corticospinal neurones in the subcortical white matter. These are termed I-waves because they are produced by synaptic activation of corticospinal neurones. The effect of TMS with an orientation of the induced current in the brain perpendicular to the line of the central sulcus and ﬂowing in a posterior to anterior direction (PA), is very similar apart from one unexpected ﬁnding, which is that the threshold difference between activation of direct and indirect activation of corticospinal neurones is reversed. At threshold for evoking a muscle twitch, PA TMS pulses evoke only I-waves; D-waves are only elicited at much higher intensities. Thus even though TES and TMS evoke electrical pulses of similar amplitude and duration are induced in the brain, they preferentially activate different targets. Overall, the characteristics of the epidural activity evoked by different forms of stimulation suggest that different populations of neurons can be activated by non-invasive brain stimulation.  TDCS CAN ALLEVIATE THE EFFECTS OF POOR SLEEP ON COGNITION A. Sterr*, J. Ebajemito. University of Surrey, UK Background: Transcranial direct current stimulation (tDCS) is an affordable and easy-to-use technology used to inﬂuence brain function. In recent years, the method has gained immense popularity as a research tool in cognitive neuroscience, and most importantly, as an intervention to boost learning and cognitive performance. While the overarching evidence-base suggests that tDCS can be an effective cognitive enhancer, lack of replicability and large individual differences pose a major challenge. In addition