7774 • The Journal of Neuroscience, September 5, 2018 • 38(36):7774–7786 Systems/Circuits Intracortical Microstimulation Modulates Cortical Induced Responses Mathias Benjamin Voigt,1,2 XPrasandhya Astagiri Yusuf,1,2,3 and XAndrej Kral1,2 1Institute of AudioNeuroTechnology and Department of Experimental Otology, Hannover Medical School, 30625 Hannover, Germany, 2Cluster of Excellence “Hearing4all”, 30625 Hannover, Germany, and 3Department of Medical Physics/Medical Technology Cluster IMERI, Faculty of Medicine Universitas Indonesia, 10430 Jakarta, Indonesia Recentadvancesincorticalprostheticsreliedonintracorticalmicrostimulation(ICMS)toactivatethecorticalneuralnetworkandconvey information to the brain. Here we show that activity elicited by low-current ICMS modulates induced cortical responses to a sensory stimulus in the primary auditory cortex (A1). A1 processes sensory stimuli in a stereotyped manner, encompassing two types of activity: evoked activity (phase-locked to the stimulus) and induced activity (non-phase-locked to the stimulus). Time-frequency analyses of extracellular potentials recorded from all layers and the surface of the auditory cortex of anesthetized guinea pigs of both sexes showed that ICMS during the processing of a transient acoustic stimulus differentially affected the evoked and induced response. Specifically, ICMS enhanced the long-latency-induced component, mimicking physiological gain increasing top-down feedback processes. Further- more, the phase of the local field potential at the time of stimulation was predictive of the response amplitude for acoustic stimulation, ICMS, as well as combined acoustic and electric stimulation. Together, this was interpreted as a sign that the response to electrical stimulation was integrated into the ongoing cortical processes in contrast to substituting them. Consequently, ICMS modulated the cortical response to a sensory stimulus. We propose such targeted modulation of cortical activity (as opposed to a stimulation that substitutes the ongoing processes) as an alternative approach for cortical prostheses. Key words: auditory cortex; cortical implant; hearing; neuroprosthetic; oscillation Significance Statement Intracortical microstimulation (ICMS) is commonly used to activate a specific subset of cortical neurons, without taking into account the ongoing activity at the time of stimulation. Here, we found that a low-current ICMS pulse modulated the way the auditory cortex processed a peripheral stimulus, by supra-additively combining the response to the ICMS with the cortical processing of the peripheral stimulus. This artificial modulation mimicked natural modulations of response magnitude such as attention or expectation. In contrast to what was implied in earlier studies, this shows that the response to electrical stimulation is not substituting ongoing cortical activity but is integrated into the natural processes. Introduction evoking action potentials in neurons close to the stimulation Intracortical microstimulation (ICMS) is widely used in neuro- electrode (Tehovnik, 1996; Clark et al., 2011; Histed et al., 2013). science to identify a causal connection between cortical neuronal In addition to basic neuroscientific research, this method has activity and a specific brain function (Cicmil and Krug, 2015). Its been used for the development of invasive neural prostheses main use is the activation of a subset of the cortical network by (Schwartz, 2004; Lebedev, 2016; Lebedev and Nicolelis, 2017). Most progress in the development of implantable cortical pros- Received April 11, 2018; revised June 19, 2018; accepted July 6, 2018. theses for humans has been achieved in the somatosensory and Author contributions: M.B.V. wrote the first draft of the paper; M.B.V., P.A.Y., and A.K. edited the paper. M.B.V. motor systems of tetraplegic patients (Aflalo et al., 2015; Flesher and A.K. designed research; M.B.V. performed research; M.B.V. and P.A.Y. analyzed data. et al., 2016; Pandarinath et al., 2017). ThisworkwassupportedbytheGermanResearchFoundation,ClusterofExcellence“Hearing4all”(EXC1077).We thank Karl-Ju¨rgen Ku¨hne and Daniela Ku¨hne for support during the experiments and Dr. Peter Hubka for extensive In neural prostheses ICMS is used to evoke a specific function discussion of the data presented herein. of the brain (e.g., elicit a percept or affect a muscle) by activating The authors declare no competing financial interests. a neuronal population that is providing this particular function. Correspondence should be addressed to Mathias B. Voigt, Institute of AudioNeuroTechnology, OE 8891, Han- In theory, activating the responsible network “naturally”, i.e., nover Medical School, Stadtfelddamm 34, 30625 Hannover, Germany. E-mail: [email protected]. DOI:10.1523/JNEUROSCI.0928-18.2018 comparable with physiological activation, would provide optimal Copyright © 2018 the authors 0270-6474/18/387774-13$15.00/0 control of the targeted cortical processing. One precondition to Voigt et al. • ICMS Modulates Induced Responses J. Neurosci., September 5, 2018 • 38(36):7774–7786 • 7775 Figure 1. Methodology. A, Photograph showing the exposed cortex and the recording electrode arrangement. The double shank recording/stimulation electrode array was inserted through a hole in the substrate of the rectangular 16-channel surface electrode array placed on A1. PSS, Pseudo-sylvian sulcus. B, Recording/stimulation channel parameters. The first 16 channels (Shank 1) of the depth electrode array could be connected to a dedicated current source. Cortical layers have been assigned to single electrodes according to literature (Wallace and Palmer, 2008) and current sourcedensityprofiles(Voigtetal.,2017).C,Schematicofthestimuluscombinationused.Auditory(condensationclick,50␮s,40dBaboveABRhearingthreshold)andelectricstimuli(biphasic,200 ␮s/phase, cathodic-leading, ϳ3 ␮A) have been presented either alone or in combination. In combined conditions the auditory stimulus was always leading the electric stimulus with a delay (⌬t) of 5, 15, or 25 ms of the electric stimulus. allow physiological-like activation is that the response to ICMS is The two response components, the evoked and induced re- integrated into ongoing cortical processing. Although the influ- sponse, are usually interpreted as corresponding to two stages ence of the network state (Buonomano and Maass, 2009)on of processing. The evoked component reflects the thalamo- cortical processing has been a well-known fact (Arieli et al., 1996; cortically conveyed bottom-up processes, whereas the induced Henry and Obleser, 2012), internal cortical processing at the mo- responses result from interaction of such thalamo-cortical inputs ment of stimulus presentation received insufficient attention. with weaker corticocortical inputs (Poort et al., 2012; Klink et al., Only recently, discussions on adapting neuroprosthetical stimu- 2017). Functionally, the induced response component likely rep- lation to ongoing cortical processes have been initiated (Panzeri resents top-down feedback processes linking external stimuli to et al., 2016). As examples of the effectiveness of such an approach, an internal cortical model of the environment, i.e., combining the effect size of transcranial magnetic stimulation increased externally driven sensory input with internally generated predic- when stimulation was confined to a specific EEG phase (Zrenner tions (Engel et al., 2001; Chen et al., 2012; Morillon et al., 2015). et al., 2018) and using the internal cortical state as an additional Low-current ICMS alone, at a current level sufficient to gen- prediction variable increased information yield from recorded erate significant local neuronal activity (Voigt et al., 2017), neuronal activity (De Feo et al., 2017), an important bottle-neck showed an evoked component, but no induced component. Add- in brain–computer interfaces (Baranauskas, 2014; Tehovnik and ing ICMS to an acoustic stimulation differentially affected oscil- Chen, 2015; Panzeri et al., 2016). latory responses: the induced responses were supra-additively Here we show that ICMS can lead to a neuronal response that amplified, whereas the evoked responses were reduced. A phase- becomes integrated into ongoing processes similar to an acoustic based response variability analysis revealed an influence of the stimulus, in contrast to substituting the physiological activity prestimulus network state on the response amplitude similarly in with artificially generated activity. We recorded activity from the ICMS and acoustic stimulation. Consequently, low-current in- surface and the depth of the primary auditory cortex (A1; Fig. 1A) tracortical microstimulation can be physiologically integrated of guinea pigs during acoustic stimulation, ICMS, and a combi- into the cortical processing and modulate cortical responses. nation of both (Fig. 1B,C). Oscillatory activity documented the expected response of A1 to transient acoustic stimuli, consisting Materials and Methods of two types of activity: an early phase-locked (“evoked”) re- Animals and preparation. Data from nine Dunkin Hartley guinea pigs sponse and a late non-phase-locked (“induced”) response. This (Crl:HA; Charles River Laboratories; 7 male, 2 female) weighing 350– has been previously described in the auditory cortex of rodents 440 g were used. Data of one additional animal (male, 500 g) were ex- (Delano et al., 2008), cats (Yusuf et al., 2017), nonhuman pri- cluded from analysis, because recordings included a secondary auditory mates