Research ReportPitch discrimination in cerebellar patients: Evidence for a sensory deficit
Introduction
The cerebellum is amongst the largest, oldest, and most structurally conserved brain regions in the vertebrate nervous system (Llinas, 1969, Matano et al., 1985; Paulin, 1993, Rilling and Insel, 1998, Marino et al., 2000, Matano, 2001, Weaver, 2005). Although classically considered a motor control organ (Luciani, 1891, Marr, 1969, Albus, 1971, Ito, 1984, Llinas, 1985, Glickstein and Yeo, 1990, Thach et al., 1992), debate about cerebellar function has been spurred by a variety of recent findings associating it with numerous nonmotor tasks and systems (Schmahmann, 1997, Ivry and Fiez, 2000, Rapoport et al., 2000, Walker et al., 2000; Vokaer et al., 2002, Bower and Parsons, 2003, Manto, 2008, Andreasen and Pierson, 2008). Associated with the wide spectrum of new data there has also been a proliferation of new hypotheses of cerebellar function, postulating a role of cerebellum in timing (Ivry et al., 2002, Ivry and Schlerf, 2008), error monitoring (Fiez et al., 1992, Ben-Yehudah et al., 2007), generation of sensory predictions (Miall, 1997), attentional and executive control (Hallett and Grafman, 1997, Akshoomoff et al., 1997, Bellebaum and Daum, 2007), verbal working memory (Chen et al., 2008, Ravizza et al., 2006, Ben-Yehudah et al., 2007), speech production and perception (Ackermann et al., 2007, Ackermann, 2008), context and response mapping (Thach, 1997, Bloedel and Bracha, 1997), state estimation (Paulin, 2005, Miall et al., 2007), and adaptive forward/inverse models (Kawato et al., 1987, Wolpert et al., 1998, Wolpert et al., 2003, Ito, 2008), among others.
In general, these new conceptions of cerebellum function tend to emphasize a cerebellar role in higher order cognitive processes, especially in humans. These ideas have been supported specifically by findings from human functional neuroimaging and neurology, with implications for functional topology (see, e.g., Riva and Giorgi, 2000, Steinlin et al., 2003, Exner et al., 2004, Tavano et al., 2007, Baillieux et al., 2008, Habas et al., 2009). For example, recent neurological and neuroimaging studies have been interpreted to suggest a fundamental cerebellar role in nonmotor aspects of temporal processing (Ivry and Fiez, 2000), olfaction (Sobel et al., 1998, Connelly et al., 2003), color discrimination (Claeys et al., 2003), kinesthetic processing (Grill et al., 1994Grill et al., 1997, Blakemore et al., 1998, Tesche and Karhu, 2000, Restuccia et al., 2001, Restuccia et al., 2007), sensory processing (Pastor et al., 2004, Harrington et al., 2004a, Harrington et al., 2004b), and auditory evoked response (Arai et al., 2003). Similarly, in higher cognition, such implications have been reported for language and verbal working memory tasks (Fiez, 1996, Desmond and Fiez, 1998, Drepper et al., 1999, Fulbright et al., 1999, Leggio et al., 2000, Marien et al., 2001, Gizewski et al., 2005, Jansen et al., 2005, Justus et al., 2005, Hokkanen et al., 2006), declarative memory (Weis et al., 2004), spatial cognition (Parsons and Fox, 1997, Fink et al., 2000, Hulsmann et al., 2003, Imamizu et al., 2003, Imamizu et al., 2004, Molinari et al., 2004, Lee et al., 2005), sustained attention (Pardo et al., 1991), and executive function (Grafman and Litvan, 1992, Hallett and Grafman, 1997, Burk et al., 1996, Brandt et al., 2004, Gottwald et al., 2004, Kalashnikova et al., 2005). In addition, there have been corresponding reports concerning development (Malm et al., 1998, Karatekin et al., 2000, Scott et al., 2001, Limperopoulos et al., 2005, Gross-Tsur et al., 2006) and a variety of sensory and cognitive functions related to thirst (Parsons et al., 2000), affect (Damasio et al., 2000, Schmahmann and Caplan, 2006, Schutter and van Honk, 2005, Anderson et al., 2005), music (Griffiths et al., 1999, Parsons, 2003, Gaab et al., 2003), pain intensity (Coghill et al., 1999), and hypercapnia and air hunger (Parsons et al., 2001).
Such roles in nonmotor or cognitive processing are also supported by anatomical evidence in monkeys showing indirect cerebellar connectivity, via thalamus, pons, and basal ganglia, with cerebral cortex (for reviews, see, e.g., Ramnani, 2006, Schmahmann and Pandya, 2008, Habas et al., 2009, Strick et al., 2009).
As a role for the cerebellum has broadened from its traditional role in motor control to a wider and wider range of motor and nonmotor functions, it has increasingly been proposed (often implicitly) that quite different computations (e.g., motor, executive, linguistic semantic, emotion) are performed in different cerebellar regions (e.g., Massaquoi and Topka, 2002). The difficulty with this proposal, as discussed by various commentators (e.g., Eccles et al., 1967, Dow, 1974, Bloedel, 1992, Ramnani, 2006, Ito, 2006), is that it assumes that distinctly different core computations are performed by a neuronal circuitry that is remarkably anatomically and physiologically uniform (Bower, 2002). While it is clear that different regions of the cerebellum receive very different types of afferent inputs, and this could serve as the basis for some kind of functional topology (e.g., Manni and Petrosini, 2004, Stoodley and Schmahmann, 2009, Timmann et al., 2009), we have been pursuing the possibility, as suggested by the remarkably uniform cerebellar cortical circuitry, that there is a single core computation which operates over many different types of information.
Based on anatomical, physiological, and model-based studies of cerebellar cortical circuitry in rats (Morissette and Bower, 1996, Hartmann and Bower, 2001, Santamaria et al., 2007, Lu et al., 2009), one of us (JMB) has proposed that the predominant direct connectivity of the cerebellum with subcortical structures and its uniformity in cortical microcircuitry and physiology are more consistent with a more fundamental role for the cerebellum underlying both higher order and motor functions (Bower, 1997a, Bower, 2002). In this view, the cerebellum is involved in regulating the acquisition of incoming sensory data across all sensory modalities, including those associated with motor as well as cognitive activities. It has further been proposed that these sensory data are evaluated in very close to real-time, with cerebellar output then rapidly influencing the peripheral structures acquiring the data (Bower and Kassel, 1990, Bower, 2002). Moreover, the overall computational aim is assumed to be to assure that the highest possible quality sensory data are obtained for use by the rest of the nervous system (Bower, 1997b, Bower, 2002, Bower and Parsons, 2003). This account predicts that cerebellar dysfunction should be apparent in the most fundamental and basic forms of sensory driven discrimination and behavior.
The purpose of this present study was to specifically test this prediction in humans by evaluating primary sensory processing function in individuals with pancerebellar degeneration. (As usual in such cases, there was no evidence in our patients for localized focal lesions of cerebellum.) In order to reduce the number of possible motor and cognitive-related complications in the interpretations of the results, we tested our hypothesis in the context of auditory perception by means of a pitch discrimination task.
Although so far as we know no human study has ever specifically tested for a purely sensory role for the cerebellum in auditory processing, cerebellar activations have been constantly reported across human functional neuroimaging studies including auditory tasks without motor and higher-order components (Griffiths and Green, 1999, Griffiths et al., 1999, Belin et al., 1998, Belin et al., 2002, van Dijk and Backes, 2003; Pastor et al., 2004, Pastor et al., 2008, Chen et al., 2008). Furthermore, quantitative meta-analysis has revealed consistent patterns of cerebellar activations that are specifically associated with the processing of auditory stimuli (Petacchi et al., 2005), suggesting that the cerebellum might have an elemental role in auditory function. The results reported here demonstrate significant elevations in pitch discrimination thresholds in cerebellar patients and show that the extent of this primary auditory sensory deficit is correlated with the severity of cerebellar degeneration as measured by ataxia. We discuss these results in the context of cerebellar function in general and cerebellar function in audition in particular.
Section snippets
Detection
Patients and controls were equally accurate at detecting audible noise bursts occurring unpredictably (patients 98% correct, controls 100% correct). This performance confirmed that patients, like controls, were alert and competent for the entire detection task, the overall duration of which equaled that of the pitch discrimination task.
Pitch discrimination
As shown in Fig. 1, mean pitch discrimination threshold in the cerebellar patients (20.9 Hz) was 5.5 times that for controls (t = 4.34, p < 0.0001). The mean
Discussion
The primary aim of this study was to test the prediction, originating from the sensory hypothesis of cerebellar function (Bower, 1997a, Bower, 1997b, Bower, 2002, Bower and Kassel, 1990, Bower and Parsons, 2003), that humans affected with cerebellar disease should have detectable deficits in fundamental auditory tasks. The present study documents an auditory deficit associated with global atrophy of the cerebellum under a range of disease conditions. Specifically, the cerebellar patients have
Patients with cerebellar degeneration
Fifteen patients who demonstrated features of degenerative cerebellar dysfunction (Trouillas et al., 1997) on examination participated in the study (Table 1). Clinical signs included dysmetria of the extremities, gait ataxia, dysarthria, as well as eye movement abnormalities. The symptoms were exclusively cerebellar in the nine patients with idiopathic or familial cerebellar cortical atrophy (Villanueva-Habas et al., 2001, Hammans, 1996, Schols et al., 1997, Nance, 1997, Klockgether et al., 1998
Acknowledgments
We are grateful to Richard Ivry, Mark Konishi, and Mark Tramo for helpful comments, to Stephen E. Grill for diagnostic assistance with patients, and to Michael Martinez for assistance with preparation of the experimental materials. This work was supported by grants from the National Institutes of Mental Health (RO1-NS37109 to L.M.P.) and the National Science Foundation (NSF 0217884 to J.M.B.).
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2019, NeuronCitation Excerpt :Pattern separation could facilitate this form of associative learning by making neural representations of different sensory inputs more distinct, ensuring that the unconditional stimulus is not mistakenly associated with similar, but not identical, cues. This hypothesis is consistent with functional evidence of the cerebellum’s involvement in sensory discrimination (Gao et al., 1996; Parsons et al., 1997, 2009), but most eyeblink conditioning studies have used a single sensory cue. A recent study found that lesioning cerebellar nuclei affected the ability of mice to discriminate between two tones in a delay eyeblink conditioning task (Sakamoto and Endo, 2013).