Neuroanatomical and neurochemical substrates of timing

Abstract

We all have a sense of time. Yet, there are no sensory receptors specifically dedicated for perceiving time. It is an almost uniquely intangible sensation: we cannot see time in the way that we see color, shape, or even location. So how is time represented in the brain? We explore the neural substrates of metrical representations of time such as duration estimation (explicit timing) or temporal expectation (implicit timing). Basal ganglia (BG), supplementary motor area, cerebellum, and prefrontal cortex have all been linked to the explicit estimation of duration. However, each region may have a functionally discrete role and will be differentially implicated depending upon task context. Among these, the dorsal striatum of the BG and, more specifically, its ascending nigrostriatal dopaminergic pathway seems to be the most crucial of these regions, as shown by converging functional neuroimaging, neuropsychological, and psychopharmacological investigations in humans, as well as lesion and pharmacological studies in animals. Moreover, neuronal firing rates in both striatal and interconnected frontal areas vary as a function of duration, suggesting a neurophysiological mechanism for the representation of time in the brain, with the excitatory-inhibitory balance of interactions among distinct subtypes of striatal neuron serving to fine-tune temporal accuracy and precision.

Figure 1

Timing in the basal ganglia. Each point represents the site of peak amplitude of a timing-induced activation cluster taken from a representative sample of motor (Bueti et al, 2008b; Garraux et al, 2005; Jahanshahi et al, 2006; Jantzen et al, 2007; Lewis et al, 2004; Rao et al, 1997; Spencer et al, 2007) and perceptual (Coull et al, 2004, 2008a; Ferrandez et al, 2003; Harrington et al, 2010; Lewis and Miall, 2003a; Livesey et al, 2007; Morillon et al, 2009; Nenadic et al, 2003; Pouthas et al, 2005; Rao et al, 2001; Shih et al, 2009; Tregellas et al, 2006) timing studies in healthy volunteers (motor=red circles; perceptual=blue triangles). Activations are located in putamen (put), caudate nucleus (caud), or globus pallidus (pall), and are shown on either (a) coronal or (b) transverse views of a standardized template brain. The intersection point of the red cross-hair represents x, y, z=0, 0, 0 mm in the Montreal Neurological Institute (MNI) coordinate space. These templates should be considered as ‘glass' brains and activations were actually spread in either the (a) rostral/caudal (range y=−15 to 18 mm) or (b) dorsal/ventral (range z=−9 to 20 mm) direction. SMA and cerebellum activations from the same sample of studies are plotted in Figures 2 and 3. Cortical (eg, prefrontal and premotor) activations from the majority of these studies are illustrated in Coull and Nobre (2008).

Figure 2

Timing in the supplementary motor area (SMA). Each point represents the site of peak amplitude of a timing-induced activation cluster taken from a representative sample (see Figure 1 for details) of motor (red circles) and perceptual (blue triangles) timing studies in healthy volunteers. Activations are located in SMA or preSMA, and are shown on a midsaggital view (range of activations x=−20 to 24 mm) of a standardized ‘glass' brain. See Figure 1 for further details. The red vertical line corresponds to the anatomical division between SMA and preSMA.

Figure 3

Timing in the cerebellum. Each point represents the site of peak amplitude of a timing-induced activation cluster taken from a representative sample (see Figure 1 for details) of motor (red circles) and perceptual (blue triangles) timing studies in healthy volunteers. Activations are shown on (a) lateral (range of activations x=−23 to −39 mm in the left hemisphere and 30–42 mm in the right hemisphere) or (b) transverse (range of activations z=−45 to −18 mm) views of a standardized ‘glass' brain. The two midline activations that can be seen on the transverse view are not included in the lateral view. See Figure 1 for further details.

Figure 4

Timing deficits in nigrostriatal-lesioned rats. Mean lever-press rate (responses/min) as a function of signal duration (s) for rats trained on a 20-s PI timing procedure during three experimental phases. The preoperative timing data are shown in the left-hand column, the postoperative data are shown in the middle column, and the postoperative -DOPA test data are shown in the right-hand column. Data for rats in the caudate-putamen (CPu) lesion group are shown in the top row, the data for the substantia nigra pars compacta (SNC) lesion group are shown in the middle row, and the data for the control lesion group are shown in the bottom row. Adapted from Meck (2006b) with permission.

Figure 5

Corticostriatal circuits for interval timing. Human functional imaging data (a) showing the corticostriatal circuits (b) implicated in interval timing. Blue lines represent dopaminergic input, green lines represent GABAergic input, and red lines represent glutamatergic input. FrOp, frontal operculum; GPe, globus pallidus external capsule; GPi, globus pallidus internal capsule; preMotor, premotor cortex; dlPFC, dorsolateral prefrontal cortex; dmPFC, dorsomedial prefrontal cortex; Par, inferior parietal cortex; Put, putamen; SMA, supplementary motor area; SNC, substantia nigra pars compacta; STN, subthalamic nucleus; VL, ventral lateral nucleus of the dorsal thalamus; VA, ventral anterior nucleus of the dorsal thalamus. IT/MT/ST, inferior/middle/superior temporal cortex. Figure 5a is adapted from Coull et al (2004).

Figure 6

Timing deficits in MSA- and NBM-lesioned rats. The postoperative timing performance of rats in a peak-interval procedure. Median peak times are plotted as a function of the first 7 days (sessions 32–38) of peak-interval retraining for rats with control operations (CON), lesions of the frontal cortex (FC), of the nucleus basalis magnocellularis (NBM), of the medial septal area (MSA), and of the fimbria-fornix (FF). Adapted from Meck et al (1987).

Figure 7

Habit formation in overtrained rats. Data for rats trained on a 50-s peak-interval (PI) timing procedure. Mean difference (mean±SEM) in peak time (s) between the paired control (CON) and methamphetamine (MAP) treatments for rats receiving either the 0.5 or 1.0 mg/kg dose of MAP. Difference measures are plotted as a function of minimal (blue), intermediate (green), or extended (purple) amounts of training in the 50-s PI procedure. Adapted from Cheng et al (2007b).

Figure 8

Ketamine ‘unlocks' habit formation. Data for rats trained on a 36-s peak-interval (PI) timing procedure. Mean response rate (responses per min) is plotted as a function of signal duration for 7-month-old rats given an extended level of training (⩾180 sessions) on a 36-s PI procedure. Blue circles indicate performance after control (CON) saline injections and red circles indicate performance after cocaine+ketamine (COC+KET—15+10 mg/kg) cocktail injections. Solid lines represent the curve-fitting results of the two conditions (blue for CON and red for COC+KET). Adapted from Cheng et al (2007a).