ReviewThe anatomy of fear learning in the cerebellum: A systematic meta-analysis
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,
References (137)
- et al.
Reward-motivated learning: mesolimbic activation precedes memory formation
Neuron
(2006) - et al.
Cerebellar function in consolidation of a motor memory
Neuron
(2002) - et al.
Functional topography of primary emotion processing in the human cerebellum
NeuroImage
(2012) - et al.
Mechanisms of cerebellar involvement in associative learning
Cortex
(2011) - et al.
Neuroanatomical and neuropsychological correlates of the cerebellum in children with attention-deficit/hyperactivity disorder—combined type
J. Am. Acad. Child Adolesc. Psychiatry
(2011) - et al.
Cerebellar networks with the cerebral cortex and basal ganglia
Trends Cogn. Sci.
(2013) - et al.
A risk variant for alcoholism in the NMDA receptor affects amygdala activity during fear conditioning in humans
Biol. Psychol.
(2013) - et al.
Predictability modulates the affective and sensory-discriminative neural processing of pain
NeuroImage
(2006) - et al.
Time and tide in cerebellar memory formation
Curr. Opin. Neurobiol.
(2005) - et al.
Neural circuitry underlying the regulation of conditioned fear and its relation to extinction
Neuron
(2008)
Activation likelihood estimation meta-analysis revisited
NeuroImage
Ventral striatal activation during attribution of stimulus saliency and reward anticipation is correlated in unmedicated first episode schizophrenia patients
Schizophrenia Res.
Prediction error in reinforcement learning: a meta-analysis of neuroimaging studies
Neurosci. Biobehav. Rev.
Cerebellum: history
Neuroscience
Anatomic connections of the fastigial nucleus to the rostral forebrain in the cat
Exp. Neurol.
Evidence of a modality-dependent role of the cerebellum in working memory? An fMRI study comparing verbal and abstract n-back tasks
NeuroImage
Mechanisms of motor learning in the cerebellum
Brain Res.
The neural representation of time
Curr. Opin. Neurobiol.
Direct activation of the ventral striatum in anticipation of aversive stimuli
Neuron
Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning
Trends Neurosci.
The role of the human amygdala in the production of conditioned fear responses
NeuroImage
Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome
Neuron
Effect of bilateral lesions of the dentate and interpositus cerebellar nuclei on conditioning of heart-rate and nictitating membrane/eyelid responses in the rabbit
Brain Res.
Acquisition of classical conditioning without cerebellar cortex
Behav. Brain Res.
Cognitive and language functions of the human cerebellum
Trends Neurosci.
Appetitive conditioning: neural bases and implications for psychopathology
Neurosci. Biobehav. Rev.
Temporal difference models and reward-related learning in the human brain
Neuron
Neurodevelopmental changes in verbal working memory load-dependency: an fMRI investigation
NeuroImage
Activation of the ventral striatum during aversive contextual conditioning in humans
Biol. Psychol.
The cerebellum optimizes perceptual predictions about external sensory events
Curr. Biol.
Long-term synaptic changes induced in the cerebellar cortex by fear conditioning
Neuron
Resting-state functional connectivity of the vermal and hemispheric subregions of the cerebellum with both the cerebral cortical networks and subcortical structures
NeuroImage
Cerebellar projections to limbic system
J. Neurophysiol.
Cerebro-cerebellar interactions underlying temporal information processing
J. Cogn. Neurosci.
Acquisition of eyeblink conditioning is critically dependent on normal function in cerebellar cortical lobule HVI
J. Neurosci.
Cerebellum and psychiatric disorders
Rev. Bras. Psiquiatr.
The role of the cerebellum in sub-and supraliminal error correction during sensorimotor synchronization: evidence from fMRI and TMS
J. Cogn. Neurosci.
Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide
Mol. Brain
Cerebellar and extracerebellar involvement in mouse eyeblink conditioning: the ACDC model
Front. Cell. Neurosci.
Fear develops to the conditioned stimulus and to the context during classical eyeblink conditioning in rats
Integr. Physiol. Behav. Sci.
Opportunities and limitations of intrinsic functional connectivity MRI
Nat. Neurosci.
Feeling anxious: anticipatory amygdalo-insular response predicts the feeling of anxious anticipation
Soc. Cogn. Affect. Neurosci.
Neural substrates underlying human delay and trace eyeblink conditioning
Proc. Natl. Acad. Sci.
Functional MRI of cerebellar activity during eyeblink classical conditioning in children and adults
Hum. Brain Mapp.
Neuroticism influences brain activity during the experience of visceral pain
Gastroenterology
Recalling word lists reveals “cognitive dysmetria” in schizophrenia: a positron emission tomography study
Am. J. Psychiatry
Cued and contextual fear conditioning for rodents
Spatiotemporal firing patterns in the cerebellum
Nat. Rev. Neurosci.
Avoiding negative outcomes: tracking the mechanisms of avoidance learning in humans during fear conditioning
Front. Behav. Neurosci.
Lobular patterns of cerebellar activation in verbal working-memory and finger-tapping tasks as revealed by functional MRI
J. Neurosci.
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These authors contributed equally to this work.