Review
The anatomy of fear learning in the cerebellum: A systematic meta-analysis

https://doi.org/10.1016/j.neubiorev.2015.09.019Get rights and content

Highlights

  • Quantitative fMRI meta-analysis of cerebellar involvement in fear learning.

  • Results showed activation in the cerebellar tonsils, lobules IV–VI, and the culmen.

  • The specific involvement of these regions in fear learning is discussed.

Abstract

Recent neuro-imaging studies have implicated the cerebellum in several higher-order functions. Its role in human fear conditioning has, however, received limited attention. The current meta-analysis examines the loci of cerebellar contributions to fear conditioning in healthy subjects, thus mapping, for the first time, the neural response to conditioned aversive stimuli onto the cerebellum. By using the activation likelihood estimation (ALE) technique for analyses, we identified several distinct regions in the cerebellum that activate in response to the presentation of the conditioned stimulus: the cerebellar tonsils, lobules HIV–VI, and the culmen. These regions have separately been implicated in fear acquisition, consolidation of fear memories and expression of conditioned fear responses. Their specific role in these processes may be attributed to the general contribution of cerebellar cortical networks to timing and prediction. Our meta-analysis highlights the potential role of the cerebellum in human cognition and emotion in general, and addresses the possibility how deficits in associative cerebellar learning may play a role in the pathogenesis of anxiety disorders. Future studies are needed to further clarify the mechanistic role of the cerebellum in higher order functions and neuropsychiatric disorders.

Introduction

The cerebellum has traditionally been predominantly implicated in motor control and coordination. However, many recent accounts have been providing evidence for a role of the cerebellum in higher order functions.

Animal studies and functional connectivity MRI studies in humans have shown that, via cortico-ponto-cerebellar and cerebello-thalamo-cortical loops, the majority of cerebellum projects to many cerebral association and limbic areas, including the prefrontal and parietal cortex, amygdala, hippocampus, hypothalamus, striatum, and brain stem (Bostan et al., 2013, Buckner et al., 2013, Schutter and Van Honk, 2005, Yeo et al., 2011). Therefore, it is not surprising that lesions of the cerebellum not only result in prominent motor symptoms, but also in impairments in executive functioning, spatial cognition, language, and changes in personality and affect (Schmahmann, 2004, Schmahmann, 2013). Consequently, in 1998, this cluster of symptoms received the name cerebellar cognitive affective syndrome (Schmahmann, 1998, Schmahmann and Sherman, 1998). Furthermore, structural and functional abnormalities of the cerebellum have also been associated with impaired mood regulation and cognitive functioning in a variety of psychiatric conditions including autism, anxiety disorders, depression and psychosis (Baldaçara et al., 2008, Fatemi et al., 2012). Finally, recent studies map various higher order processes, such as executive functioning, language, spatial and emotional processing, to distinct regions of the cerebellum (Stoodley et al., 2012; Stoodley and Schmahmann, 2009, Stoodley and Schmahmann, 2010, Stoodley et al., 2010).

Preclinical studies have pointed toward a role of the cerebellum in different forms of associative learning. Data from animal studies suggest that the cerebellum is involved in motor learning, such as eyeblink conditioning (Boele et al., 2009, Koekkoek et al., 2003, Koekkoek et al., 2005, Lavond et al., 1984, Lee and Kim, 2004; Thompson and Steinmetz, 2009; Timmann et al., 2010) and adaptation of the vestibulo-ocular reflex (De Zeeuw and Yeo, 2005, Ito, 2000). However, several experimental animal studies predominantly employing the classical fear conditioning paradigm also implicate the cerebellum in emotional learning (Timmann et al., 2010). Lesion studies refine these findings by showing that lesions of the vermis result in impaired acquisition and retention of fear-conditioned autonomic responses as well as in attenuation of fear-related behaviors (Supple and Kapp, 1993, Supple et al., 1987a). Furthermore, blockade of the cerebellar vermis after fear learning produces amnesia, which has been interpreted as interfering with storage and/or memory trace retrieval. In addition, fear learning has been shown to induce long-term potentiation (LTP) in parallel fibers to Purkinje cells in vermal lobules V–V1 (Sacchetti et al., 2004, Sacchetti et al., 2007). LTP in these areas is assumed to be related to the consolidation of fear memories (Gao et al., 2012), akin to the function of an LTP mechanism that takes place in amygdala and hippocampus (Bliss and Collingridge, 2013, Rogan et al., 1997, Sacchetti et al., 2001). However, a recent study in cerebellar mouse mutants has shown that impairments in Purkinje cell plasticity did not affect fear responses during both cued and contextual conditioning (Galliano et al., 2013), even though it did result in learning deficits when a cognitive task with temporal constraints was employed (Rahmati et al., 2014). These results suggest that the cerebellum is essentially concerned with tasks requiring precise temporal accuracy (Rahmati et al., 2014, Yamaguchi and Sakurai, 2014).

Similar to the animal literature, the role of the cerebellum in human fear learning has received relatively limited attention. Possibly, the role of the cerebellum in higher order processes is more pronounced in the human than in the murine cerebellum (Galliano et al., 2013), which could be a consequence of the enlargement of the ventral dentate nucleus and related cerebellar cortical hemispheric regions, paralleling the enlargement of the prefrontal cortex (Leiner et al., 1993, Matano, 2001, Strick et al., 2009). Even though the cerebellum has been pointed out as one of the regions often activated in human fear-conditioning paradigms (Sehlmeyer et al., 2009), few studies to date have explored which specific cerebellar regions are involved in human fear learning (Frings et al., 2002, Kattoor et al., 2014). Lesion studies and fMRI studies of healthy individuals suggest a role of the vermis in fear-conditioned potentiation of motor and autonomic responses (Frings et al., 2002, Maschke et al., 2000, Maschke et al., 2002), whereas activation in left lobule HV1 is proposed to be associated with the acquisition of fear (Frings et al., 2002). Furthermore, many fear learning paradigms involve sensorimotor and timing components next to emotional learning (Glickstein et al., 2009; Rahmati et al., 2014), thus further obfuscating the investigation into the primary role of the cerebellar regions in the purely emotional, non-motor aspects of the fear learning process. As a result, a decisive account of the precise regions and functional contribution of the cerebellum involved in human fear learning remains to be determined.

Aim of the present meta-analytic study is to examine the results of all available human fMRI studies in a systematic fashion, and thus shed light on the precise location of the cerebellar contributions to fear learning in the healthy population. Therefore, in order to unequivocally determine the locus of cerebellar activity associated with fear learning we gathered, reviewed and analyzed all published functional magnetic resonance imaging studies on this subject.

Section snippets

Step 1: Literature review

Two researchers (IL, ZK) independently performed the search, screening, selection and coding steps of this meta-analysis. The PubMed database was searched for words ‘emotional learning’ or ‘aversive learning’ and additionally for ‘fear conditioning or ‘fear learning’ AND ‘imaging’, with the filter for, ‘human’. Articles published until December 2013 were screened on titles, abstracts and/or full texts: the search revealed in total 2128 articles. The following criteria for the inclusion of

Results

The results of the ALE meta-analysis of the 21 studies on fear learning revealed six clusters of significant activation-likelihood located in the cerebellum. The activation found was roughly symmetrical across the cerebellar hemispheres. The largest peak encompassed left lobules HIV–V, HVI, and, lobule HIX. The second peak was found in the culmen. Other peaks were found in the left and right lobules HIX and right lobules HIV–V. Table 3 shows the peak coordinates, cluster sizes, peak ALE values

Discussion

The aim of this meta-analysis was to synthetize findings from fMRI studies reporting cerebellar activation during fear conditioning in healthy individuals in order to decisively map the neural response associated with conditioned stimulus onto the cerebellum. The results of this ALE meta-analysis show six specific cerebellar regions involved in fear learning: the culmen, right and left lobule HIV–V and left lobule VI, and right and left lobule HIX.

The largest peak encompassed the lobules HIV–V,

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    These authors contributed equally to this work.

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