Understanding how brains process sensory signals in natural environments is one of the key goals of twenty-first century neuroscience. While brain imaging and invasive electrophysiology will play key roles in this endeavor, there is also an important role to be played by noninvasive, macroscopic techniques with high temporal resolution such as electro- and magnetoencephalography. But challenges exist in determining how best to analyze such complex, time-varying neural responses to complex, time-varying and multivariate natural sensory stimuli. There has been a long history of applying system identification techniques to relate the firing activity of neurons to complex sensory stimuli and such techniques are now seeing increased application to EEG and MEG data. One particular example involves fitting a filter—often referred to as a temporal response function—that describes a mapping between some feature(s) of a sensory stimulus and the neural response. Here, we first briefly review the history of these system identification approaches and describe a specific technique for deriving temporal response functions known as regularized linear regression. We then introduce a new open-source toolbox for performing this analysis. We describe how it can be used to derive (multivariate) temporal response functions describing a mapping between stimulus and response in both directions. We also explain the importance of regularizing the analysis and how this regularization can be optimized for a particular dataset. We then outline specifically how the toolbox implements these analyses and provide several examples of the types of results that the toolbox can produce. Finally, we consider some of the limitations of the toolbox and opportunities for future development and application.

People routinely hear and understand speech at rates of 120-200 words per minute [1, 2]. Thus, speech comprehension must involve rapid, online neural mechanisms that process words' meanings in an approximately time-locked fashion. However, electrophysiological evidence for such time-locked processing has been lacking for continuous speech. Although valuable insights into semantic processing have been provided by the "N400 component" of the event-related potential [3-6], this literature has been dominated by paradigms using incongruous words within specially constructed sentences, with less emphasis on natural, narrative speech comprehension. Building on the discovery that cortical activity "tracks" the dynamics of running speech [7-9] and psycholinguistic work demonstrating [10-12] and modeling [13-15] how context impacts on word processing, we describe a new approach for deriving an electrophysiological correlate of natural speech comprehension. We used a computational model [16] to quantify the meaning carried by words based on how semantically dissimilar they were to their preceding context and then regressed this measure against electroencephalographic (EEG) data recorded from subjects as they listened to narrative speech. This produced a prominent negativity at a time lag of 200-600 ms on centro-parietal EEG channels, characteristics common to the N400. Applying this approach to EEG datasets involving time-reversed speech, cocktail party attention, and audiovisual speech-in-noise demonstrated that this response was very sensitive to whether or not subjects understood the speech they heard. These findings demonstrate that, when successfully comprehending natural speech, the human brain responds to the contextual semantic content of each word in a relatively time-locked fashion.