Brain-machine interface research Mikhail AL et al. based on an instruction, in the format of spatiotemporal pattern of ICMS, delivered directly to the animals’ S1. The monkeys were implanted with multiple microwire arrays in several cortical areas. The dorsal premotor cortex (PMd) and primary motor cortex (M1) arrays were used to extract motor commands, while the primary somatosensory cortex (S1) array was employed as the main target for ICMS. The electrodes chosen for ICMS yielded recorded S1 neurons with clear receptive fields located on the ventral aspect of the second, third and fourth digits and palm pads. Biphasic current pulses were injected into S1 through these electrode pairs synchronously at 30 to 60 Hz. We simultaneously recorded the electrical activity of 50–200 cortical neurons. The monkeys learned to perform in BMI control with and without using the joystick. Moreover, in our recent study,28 ICMS served as an artificial sense of active touch as it conveyed to the monkeys the properties of virtual objects that the actuator (computer cursor or a virtual image of a monkey arm) touched. Two monkeys learned to operate this new apparatus, without any need to move their own limbs or use visual feedback to solve the task. Thus, as a result of converging principles of motor and sensory neuroprosthetics, we have demonstrated the feasi- bility of moving from a BMI to a brain-machine-brain interface in which artificial actuators and brain tissue are connected bi-directionally, without any meaningful inter- ference or constraint imposed by the physical limits of the subject’s body. POSITION SENSE Having created a paradigm for introducing an artificial sense of touch to our BMIs, the next goal of the DUCN is to develop neuroprosthetic limbs that incorporate an artificial sense of position. Position sense is of great importance for clinical applications because ideal prosthetic limbs should be perceived as natural extensions of the users’ bodies. Normally, such positional signals are provided by the afferents of muscles, joints and skin. Afferent information ascends to the brain where it is eventually transformed into representations encoding limb position in different coordi- nate frames, such as body-centered and external space- centered coordinates.41,42 The complexity of spatial proces- sing in the brain makes the task of creating an artificial position sense particularly difficult. Theoretically, artificial proprioception could be implemented in a straightforward way by applying microstimulation to the somatosensory cortex or thalamus that reproduces individual joint angles of an artificial arm. The subject would then experience sensation of many DOFs of the artificial arm and would be able to perceive its spatial orientation. However, practical realization of such position sense would be problematic because of numerous uncertainties in choosing the trans- formation from the stimulation patterns to the joint angles. Given the complexity of cortical processing of propriocep- tive information,43 it would be impossible to implement such transformation as a precise mapping from the arm joints to the brain somatosensory map. It is also question- able if the user would be able to transform the stimulation patterns designed to mimic individual joints into a coherent position sense. Additionally, certain centrally generated components of normal position sense, such as corollary 28 CLINICS 2011;66(S1):25-32 discharges,44 would be difficult to incorporate in such implementation. Because of these foreseen difficulties in the straightfor- ward implementation of an artificial position sense, we chose a simpler and more feasible approach in which stimulation of S1 is not initially coupled to the orientation of the limb position, but instead represents 3D spatial locations to which the subject is required to reach. In this approach, the subject starts with learning how ICMS of cortical somatotopic representations of the body is mapped to a 3D space. Once the learning of such mapping is perfected, the same ICMS pattern is used to represent the spatial location of the endpoint of a prosthetic limb, fulfilling the goal of providing a limb neuroprosthetic with a position sense. This experimental design bears similarity to the studies on sensory substitution in which visual information was conveyed by the stimulation of skin surfaces,45–47 with the difference that, instead of using peripheral receptors as the entry point for the artificial sensory channel, we opted to deliver the information directly to the somatosensory cortex or thalamus. We expect that similarly to sensory substitu- tion using peripheral stimulation, training with stimulation of the somatosensory areas of the brain would eventually give rise to an artificial position sense that represents external space. Furthermore, we expect that as such position sense becomes coupled to the position of a virtual image of a monkey arm (monkey avatar), monkeys will develop an artificial proprioception sense capable of guiding their movements thereafter. OPTOGENETICS Our initial approach to sensorizing neuroprosthetic limbs was based on ICMS, which involves delivering small pulses of current through microelectrodes directly into the sensory areas of the brain.28,29,40 Although this technique proved to be efficient in bi-directional BMIs, it has relatively low spatial resolution48 and produces electrical artifacts that saturate neural recording channels,49 causing problems for extracting neural activity both during and after this period, as it typically occludes 5–10 ms of neural data per pulse. ICMS acts on both fibers and neurons, and neurons in the stimulated area may become inhibited instead of being excited.50 A further problem is that ICMS pulses have to be precisely balanced, otherwise an unbalanced current injec- tion could cause damage to the neural tissue stimulated by this procedure. To explore an alternative method for sensorizing neuro- prosthetics, we have started to design a cortical multi- channel stimulator based on optogenetics—a new technique for the stimulation of neurons. Optogenetics is based on genetically modified ion channels that respond directly to light.51 These light-gated ion channels, such as Channelrhodopsin-2 (Chr-2), allow precise, millisecond control of specific neurons.52,53 This technique eliminates most of the key problems associated with ICMS: there is no associated electrical artifact to interfere with the electro- physiological recordings, nor any tissue damage from the current injection. It also allows for finer control of the spatial pattern of activation. We expect that multichannel optoge- netic stimulation combined with multichannel neuronal recordings will allow us to develop an artificial position sense in monkeys and to study the neuronal mechanisms involved in it. Bi-directional BMIs based on such a design