Physiological brainstem mechanisms of trigeminal nociception: An fMRI study at 3T

The brainstem is the major site of trigeminal pain processing and modulation and has been discussed as a main player in the pathophysiology of various headache disorders such as migraine or cluster headache (Afridi et al., 2005, Bahra et al., 2001, Denuelle et al., 2007, Stankewitz et al., 2011, Weiller et al., 1995). Previous anatomical and electrophysiological studies in animals and humans have been able to identify the primary hubs of the trigeminal pain pathway: a nociceptive stimulus enters the central nervous system via the trigeminal ganglion (TG). The stimulus is then conducted to the spinal trigeminal nuclei (sTN) and further to the ventral posterior medial nucleus of the thalamus (VPM) and to the primary somatosensory cortex (S1) (Wallenberg, 1900, Carpenter and Hanna, 1961, Stewart and King, 1963, Tiwari and King, 1974, Hayashi, 1985a, Hayashi, 1985b, Capra and Dessem, 1992, Usunoff et al., 1997, DaSilva et al., 2002). Nociceptive signals are modulated by a network of various brainstem centers: the descending pain modulating system, including the periaqueductal gray matter (PAG), the hypothalamus (HT), the red nucleus (RN), the substantia nigra (SN), the locus coeruleus (LC), the rostral ventromedial medulla and the lateral reticular formation of the midbrain, including the cuneiform nucleus (CNF) (Millan, 2002). Whereas the anatomy and fiber connections between the aforementioned brainstem centers are reasonably well understood from anatomical and electrophysiological work (Basbaum et al., 2009, Burstein et al., 1998, Edvinsson, 2011, Millan, 2002, Noseda et al., 2008, Noseda and Burstein, 2013), their functional activity and their interactions in humans following trigeminal nociceptive stimulation remain a subject of current research. Previous functional imaging studies in humans have been able to identify the spinal trigeminal nuclei, the VPM and SI as the major conduction sites of painful trigeminal stimuli (DaSilva et al., 2002, Stankewitz et al., 2010). However, the aforementioned studies commonly investigated both cortical and subcortical areas without a special focus on the brainstem. As a consequence, brainstem activations following trigeminal nociceptive stimulation in most studies could either not be found at all (Boyle et al., 2007, Iannilli et al., 2008) or have been very unspecific without a clear differentiation between different brainstem nuclei (Hummel et al., 2005). Thus a more focused imaging technique of the human brainstem in combination with human models of headache attacks is an indispensable tool in pathophysiologic and therapeutic headache research. However, as the brainstem is an area directly surrounded by large blood vessels and cerebrospinal fluid, it is much more susceptible to cardiac and respiratory noise than other regions of the brain. Additionally, as the different nuclei of this brain area lie in a close spatial relationship to each other, a high spatial resolution is mandatory to assign found activations to single brainstem nuclei. This however decreases the signal to noise ratio (SNR). As a result a special noise correction technique is mandatory. To address these points and to achieve a more detailed insight into mechanisms of trigeminal nociception within the brainstem, we employed a well-established protocol of nociceptive trigeminal stimulation in combination with an optimized approach to brainstem fMRI using an adapted field of view and a high in-plane resolution in combination with retrospective correction of general image noise by spatially adaptive nonlocal means filtering (Coupé et al., 2006) and retrospective correction of physiological noise (Deckers et al., 2006). We present detailed insight into brainstem mechanisms of trigeminal nociception.