Frontostriatal Gating of Tinnitus and Chronic Pain

Abstract

Tinnitus and chronic pain are sensory-perceptual disorders associated with negative affect and high impact on well-being and behavior. It is now becoming increasingly clear that higher cognitive and affective brain systems are centrally involved in the pathology of both disorders. We propose that the ventromedial prefrontal cortex and the nucleus accumbens are part of a central 'gatekeeping' system in both sensory modalities, a system which evaluates the relevance and affective value of sensory stimuli and controls information flow via descending pathways. If this frontostriatal system is compromised, long-lasting disturbances are the result. Parallels in both systems are striking and mutually informative, and progress in understanding central gating mechanisms might provide a new impetus to the therapy of tinnitus and chronic pain.

Keywords: Tinnitus; chronic pain; nucleus; ventral striatum; ventromedial prefrontal cortex.

Figure 1. Schematic of brain structures involved in tinnitus and chronic pain

Block diagrams of relevant brain structures are shown for tinnitus (left) and chronic pain (right). Please note that the diagrams primarily show the structures and connections most relevant in the context of the proposed concept, but are not exhaustive. Abbreviations: A1, A_np: primary and nonprimary auditory cortex; S1, S2: primary and secondary somatosensory cortex; PFC: prefrontal cortex; vmPFC: ventromedial prefrontal cortex; NAc: nucleus accumbens; Amyg: amygdala; M/ACC: mid/anterior cingulate cortex; Hc: hippocampus.

Figure 2. Reductions in gray matter found in tinnitus and chronic pain

The location of peak voxels and local maxima of gray-matter reduction found in tinnitus and chronic pain studies are represented on the medial surface of a T1-normalized brain template. Peak voxels that are situated on the lateral surface of the brain are not displayed. Left: Locations of reduction in gray-matter volume in tinnitus. Green: Mühlau et al. [13]; orange: Leaver et al. [15]; pink: Husain et al. [49]; brown: Landgrebe et al. [17]. Right: Locations of reduction in gray-matter volume in chronic pain. Red: Smallwood et al. [24]; light blue: Cauda et al. [25]; yellow: May et al. [23] (migraine/headache); purple: May et al. [23]; dark blue: Baliki et al. [26] (chronic back pain and knee osteoarthritis). Note that in the meta-analysis of May et al. [23], all available stereotactic coordinates were aggregated using GingerALE 2.0 (http://www.brainmap.org/index.html), and exact coordinates could therefore not be retrieved. As a result, one symbol falls on the genu of the corpus callosum, and an enlarged symbol was used in another instance.

Figure 3. (Key Figure): Frontostriatal circuit with its main inputs and outputs (exemplified here for tinnitus)

The nucleus accumbens (NAc) receives excitatory input from the neocortex, which ends on GABAergic spiny projection neurons (filled symbol) directly and via inhibitory interneurons [149]. In addition, the NAc receives modulatory input from (among others) dopaminergic [150] and serotonergic [151] structures and forms a processing loop for the valuation of sensory stimuli with the subcallosal anterior cingulate cortex (scACC) and, via the ventral pallidum (VP), with thalamic nuclei in the limbic system, such as the mediodorsal nucleus (see also [14]). The amygdala (shown here without subdivisions and intrinsic circuitry) can bias this valuation system by providing emotional information [106]. The result of this valuation is used by the ventromedial prefrontal cortex (vmPFC) to send a descending signal to subcortical structures with mostly inhibitory effects. These can be achieved via inhibitory interneurons in the amygdala or NAc or via the thalamic reticular nucleus (TRN). The latter can attenuate thalamo-cortical transmission in sensory thalamic nuclei in a highly selective manner, thus exerting powerful gain control [16,100-102]. See [152] for more details on corticostriatal connectivity. Abbreviations as in Fig. 1; in addition: TRN: thalamic reticular nucleus; VTA: ventral tegmental area; GABA: gamma-aminobutyric acid; vol: volume. Lines in green (with pointed endings) represent excitatory connections (glutamate); lines in red (with flat endings) refer to inhibitory connections (GABA). A direct GABAergic projection from the basal ganglia back to frontal cortex is currently hotly debated [153] and is shown as a dashed line.