Differential Input of the Supplementary Motor Area to a Dedicated Temporal Processing Network: Functional and Clinical Implications

The ability to track the temporal structure of events in a dynamic environment is crucial to cognition and action alike. In order to guide timely reactive and proactive behavior the individual has to draw upon some internal representation of temporal relations or temporal structure. Here an event may be defined as a perceived change in the formal structure of the environment, i.e., the identity (“what”) or the position (“where”) of an object. In turn, the temporal relation between events may be defined as the temporal structure (“when”) of the environment. Temporal structure develops on different timescales (Buonomano, 2007). For example, starting and stopping to walk from one position to another marks events with a certain temporal relation, typically in the seconds-to-minutes range. Yet, contact of a foot with the surface establishes another kind of event, with successive steps marking temporal structure in the milliseconds range. Such marking of the beginning and the end of an action sequence is represented in prefrontal and supplementary motor cortices (Fujii and Graybiel, 2003; Shima and Tanji, 2006). However, the question arises as to whether the perception and production of the corresponding temporal structure in the milliseconds-to-seconds range is intrinsic or whether it is based on an explicit representation generated by a dedicated temporal processing system (Karmarkar and Buonomano, 2007; Ivry and Schlerf, 2008; Spencer et al., 2009). Compelling evidence suggests that temporal processing, i.e., the neural mechanisms that engage in encoding, decoding, and evaluating of temporal structure, relies on brain regions involved in action control: the cerebellum, the basal ganglia, and the supplementary motor area (SMA; for a review see Coull et al., 2011). However, a high-level function such as action control incorporates various lowerlevel processes. This becomes apparent if one considers the role of the SMA in action control. Located bilaterally in Brodmann area 6 of the medial frontal lobe, the SMA has traditionally been linked to the planning and the preparation of future, sequential, and rhythmic performance, as well as to the initiation, inhibition, preservation, and repetition of action (Brickner, 1939; Penfield, 1950; Goldberg, 1985; Tanji, 1996). Crucially, SMA lesions affect non-verbal and verbal behavior. They may result in the inability to speak, stuttering, hesitations, “slowliness,” the prolonging of sounds, and persistent dysfluency, phenomena, which impact the continuous flow or pacing, i.e., the rate and rhythm of speech (Jonas, 1981; Ziegler et al., 1997). These phenomena corroborate a role of the SMA in controlling temporal relations in action, but leave open whether temporal processing is intrinsic or explicitly dedicated. However, evidence for a dedicated temporal processing system comes from studies, which confirm a role of the SMA not only in the production, but also in the perception of temporal structure (Macar et al., 2002; Ferrandez et al., 2003; Coull et al., 2004). The SMA, or more specifically, the SMA and its striato-thalamic connections, is a candidate neural substrate for a “temporal accumulator” engaged in the encoding of temporal structure (Akkal et al., 2004; Pouthas et al., 2005; Macar et al., 2006; Casini and Vidal, 2011). Furthermore, considering a structural differentiation of the SMA into a rostral pre-SMA and a more caudal SMA-proper (Picard and Strick, 2001), it has been suggested that pre-SMA is essential for attentiondependent quantification (Coull et al., 2004; Macar et al., 2004) or “tagging” of temporal structure (Pastor et al., 2006). Such functional specification based on structural differentiation may reflect an interaction within a distributed temporal processing network, which is determined by unique connections from the pre-SMA and the SMA-proper to other cortical and subcortical regions (Johansen-Berg et al., 2004; Akkal et al., 2007). Among others, connections from the pre-SMA target the prefrontal cortex, while connections from the SMA-proper target motor and pre-motor cortices (JohansenBerg et al., 2004). However, the thalamus connects both pre-SMA and SMA-proper to essential nodes within a dedicated temporal processing network, namely the cerebellum and the basal ganglia. Connections from both SMA subareas to the basal ganglia maintain a rostro-caudal gradient in their structural and functional organization and establish a cortico-striato-thalamo-cortical looped system (Johansen-Berg et al., 2004; Draganski et al., 2008). Connections between the pre-SMA and the cerebellum originate in the non-motor part of the cerebellar dentate nucleus, whereas connections to the SMA-proper originate in its motor part (Dum and Strick, 2003; Akkal et al., 2007). In general, the SMA receives more input from the basal ganglia than from the cerebellum (Akkal et al., 2007). Next to direct subcortico-subcortical connections (Hoshi et al., 2005; Bostan and Strick, 2010; Bostan et al., 2010), this structural embedding of the pre-SMA and the SMA-proper into subcortico-thalamo-cortical processing streams instantiates interaction between the cerebellum and the basal ganglia in temporal processing (Schwartze et al., in press). Note, that the role of the thalamus as a mere relay station is therefore simply underspecified (see Sherman, 2007). Rather, the thalamus should