The cerebellum is a highly organized brain region located in the posterior fossa, and most known for its role in motor coordination, and bodily posture and balance (reviewed in Caulfield and Servatius, 2013; Kandel et al., 2013). While accounting for only 10% of the total brain volume, the cerebellum harbors more neurons than the rest of the brain (Azevedo et al., 2009). By its anteroposterior direction, the cerebellum is divided in two hemispheres and its midline area, the vermis, forming in tandem the three main lobes: flocculonodular, anterior and posterior lobes, subdivided in lobules I-X that constitute the distinctive folia (Apps and Hawkes, 2009; Schutter, 2020). The cerebellar cortex congregates gray matter in its outer part, while white matter is found in the innermost part, innervating the three deep cerebellar nuclei: dentate, fastigial, and interposed nuclei (Kandel et al., 2013).

Beyond motor-related functions, cumulative evidence support that the cerebellum modulates higher order and executive functions, including prediction and error-based learning (Butcher et al., 2017; Sokolov et al., 2017; Uehara et al., 2018), associative and implicit learning (Timmann et al., 2010), episodic (Andreasen et al., 1999; Habas et al., 2009; Almeida et al., 2023) and working (Fafrowicz et al., 2023) memory systems, language (Murdoch, 2010; Mariën and Borgatti, 2018; King et al., 2023), as well as emotion regulation (Baldaçara et al., 2008; Lange et al., 2015; Caria and Grecucci, 2023). Lesion studies of the posterior cerebellum led to the description of the cerebellar cognitive affective syndrome (Schmahmann and Sherman, 1998) with a suggested cerebellar regulatory role in emotion and cognition through reciprocal connections with limbic and prefrontal regions.

Fear is a biologically basic emotion that has attracted considerable research interest due to its relevance for many clinical disorders, and the cerebellum is interconnected to brain regions comprising the fear circuitry (Apps and Strata, 2015). Animal and human studies have shown that the cerebellum is involved in fear conditioning and fear memories (Sacchetti et al., 2005; Timmann et al., 2010; Lange et al., 2015; Strata, 2015; Adamaszek et al., 2017; Frontera et al., 2020), which could be tied to the etiology of anxiety, trauma and stress-related disorders. Anxiety disorders are characterized by excessive fear and avoidance in presence of stimuli perceived as threatful, as well as heightened anticipation of threatening future events. Several clinical features are shared with post-traumatic stress disorder (PTSD) including fear and avoidance, hyperarousal, increased autonomic response, psychosomatic symptoms and trauma-related aversive memories. PTSD, which was separated from anxiety disorders in the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (American Psychiatric Association, 2013), is further characterized by hypervigilance and difficulties in maintaining concentration (Peters et al., 2021), and by difficulty in discriminating safety from threat cues (Williamson et al., 2021). The global lifetime prevalence rates have been estimated to 28.8% for anxiety disorders and 3.9% for PTSD (Kessler et al., 2005; Koenen et al., 2017). Comorbidity with other disorders, such as depression, is common (Whiteford et al., 2013).

The cerebellum has been largely understudied in comparison to traditional limbic regions like the amygdala, but recent imaging research findings indicate that the cerebellum is involved in the pathophysiology of anxiety disorders including social anxiety disorder (SAD), generalized anxiety disorder (GAD), panic disorder (PD), specific phobia (SP), as well as PTSD. Anxiety patients have been reported to display both altered cerebellar activity and connectivity with corticolimbic areas, and changes have been found after pharmacological interventions with antidepressants (e.g., Chin and Augustine, 2023) and psychological interventions such as cognitive behavioral therapy (e.g., Kindred et al., 2022). There is evidence of hyperactivity both in the cerebellum and amygdala in SAD patients (Tillfors et al., 2002; Evans et al., 2008), higher cerebellar baseline activity in PD (Sakai et al., 2005) and increased cerebellar activity in PTSD (Wang et al., 2016), although mixed results are found across disorders.

While it can be hypothesized that individual differences in cerebellar activation underlie reactivity to stressors (Moreno-Rius, 2019) and the risk for developing anxiety and stress-related disorders (Caulfield and Servatius, 2013), a clear understanding of how the cerebellum contributes to excessive anxiety and stress is lacking. The aim of this mini-review was to describe the main findings, at the cerebellar level, of human neuroimaging studies using structural (sMRI) or functional (fMRI) magnetic resonance imaging, in adult patients suffering from PTSD or anxiety (SAD, GAD, PD, SP) disorders.

Only original MRI research papers published in peer-reviewed English-language journals reporting findings in the cerebellum were considered. An advanced electronic literature search in PubMed database¹ without time restriction was carried out by using the following terms with the Boolean operator AND: “((cerebellum) AND (anxiety)) AND (MRI)” (290 results); “[(cerebellum) AND (stress)] AND (MRI)” (284 results). Additionally, advanced sub-searchings were performed for each of the target disorders: “cerebellum AND acute stress disorder” (n = 34); “cerebellum AND PTSD” (n = 94); “cerebellum AND generalized anxiety disorder” (n = 135); “cerebellum AND social anxiety disorder” (n = 69); “cerebellum AND panic disorder” (n = 24); “cerebellum AND specific phobia” (n = 18). Furthermore, recent review papers and citations were scanned for non-detected original trials, and 11 studies were added from 39 additionally scanned research articles. Figure 1 shows a flow diagram of the screening process. Research studies using sMRI or fMRI, with adult participants (>18 years of age) that had received a clinical diagnosis, in either patient-control or pre-post-treatment comparisons were included. Exclusion criteria were research articles that used: (I) another neuroimaging modality than sMRI or fMRI; (II) pediatric or adolescent populations, or healthy individuals only; (III) neuropsychiatric disorders different than the targeted PTSD/anxiety disorders; and (IV) meta-analyses, reviews or case reports.

From a total of 987 papers screened, 49 papers matching inclusion/exclusion criteria were selected: PTSD (n = 30), PTSD + SAD (n = 1), SAD (n = 9), GAD (n = 2), PD (n = 4), SP (n = 3). The total number of patients was 1,494 (600 males/894 females). A descriptive summary and imaging results are presented in Supplementary Table 1 (task-based fMRI studies) and Supplementary Table 2 (resting state rs-fMRI and/or sMRI studies) in Supplementary material. Task-based fMRI studies mainly used disorder-relevant challenges to obtain the neural activation maps during task (disorder-relevant stimuli) compared to control conditions (neutral stimuli). Most rs-fMRI studies measured functional connectivity (FC) between the cerebellum and other brain regions (intrinsic connectivity distribution), or at intra-cerebellar network level (intra-network FC). Structural MRI studies mostly used voxel-based-morphometry (VBM) to identify variations in gray matter volume (GMV). The vast majority of studies were cross-sectional comparing patients vs. controls while some were treatment studies evaluating pharmacotherapy and/or psychological interventions with pre-post within-group evaluation or treatment vs. placebo comparisons in patients. Two studies also used a machine learning approach to classify groups.

It has been increasingly recognized that the functions of cerebellum extend into emotions, including fear and anxiety. The cerebellum could work as a complementary region to the amygdala in emotional reactivity and modulation (Strata, 2015), and the amygdala-cerebellum reciprocal link has been shown to be aberrantly functioning in post-traumatic stress and anxiety disorders (Nicholson et al., 2015; Thome et al., 2017; Sandman et al., 2020; Du et al., 2021; Park et al., 2022). Hence, this mini-review evaluated functional (task activity, resting state connectivity) and structural (gray matter) findings on the cerebellum reported in MRI studies of patients with PTSD or anxiety disorders.

Results showed that PTSD was the single most studied disorder, targeted in 63% of the included studies. The cerebellum tends to show hyperactivation in the task-based fMRI studies. Among the cerebellar subregions, the vermis (Ke et al., 2015, 2016), lobule VI (Rabellino et al., 2016; Naegeli et al., 2018), and crus I (Rabellino et al., 2018; Yuan M. et al., 2018; Awasthi et al., 2020; Nicholson et al., 2020), emerge as key cerebellar distinctive structures that could be involved in the symptomatology or developmental course of PTSD. The vermis has been highlighted for its role in enhancing episodic memory of emotional stimuli (Fastenrath et al., 2022), its contribution to fear-related memories maintenance (Strata et al., 2011) and is considered to be the limbic cerebellum (Klein et al., 2016).

It is noteworthy that the baseline vermis and left cerebellum hyperactivation in PTSD decreased over a long-term perspective, with baseline vermis activity being predictive of symptom improvement (Ke et al., 2016). It could be expected that successful treatment would contribute to downregulation of emotion-related cerebellar/vermal activity, although treatment effects should be further explored, especially considering the divergent findings noted for hydrocortisone interventions aimed at targeting the glucocorticoid system (Douglas et al., 2019; Metz et al., 2019; Schwab et al., 2020).

Across the anxiety disorders, results were mixed with regard to cerebellar hyper- or hypoactivation in task-based fMRI trials. Altered amygdala to cerebellum FC was noted in GAD (Park et al., 2022) and also following psychological intervention in SAD (Sandman et al., 2020). In SP, even when considering different types like blood and spider phobia, fMRI results seemed more homogeneous, showing increased activation of the left cerebellum and lobule VI. The cerebellar lobule VI is thought to be decisive for higher-order cognitive functions, such as working memory (Lange et al., 2015; Ashida et al., 2019). Studies supporting a functional topographic organization of the human cerebellum have noted idiosyncratic subregions to modulate sensorimotor, cognitive, and limbic processes (Stoodley and Schmahmann, 2010; Habas and Manto, 2018) with possible left-right lateralization (Baillieux et al., 2010). Following this, cerebellar activation patterns would depend largely on type of task or context (Schmahmann et al., 2019) which varied notably in the fMRI studies evaluated here.

With regard to resting-state fMRI findings, PTSD is marked by reduced FC between the cerebellum and the central executive network (CEN) (Vuper et al., 2021), in which the cerebellar crus II takes part. Disrupted CEN might reflect difficulty in concentration in adults with PTSD, and it has previously been shown to be affected in GAD (Kolesar et al., 2019). Altered crus I, that participates in the default mode network (DMN) (Halko et al., 2014), was found by Yin et al. (2011) measured with amplitude of low-frequency fluctuations. The DMN, also composed by cerebellar lobule IX, is further involved in mental imagery and long-term episodic memory processes (Habas et al., 2009), that are potential clinical features of PTSD (Zlomuzica et al., 2018; Petzold and Bunzeck, 2022; Almeida et al., 2023). Disrupted FC between the cerebellum and the dorsal anterior cingulate cortex (Chen et al., 2019) may reflect altered motor and cognitive processing involved in reward (Bush et al., 2002), while a reduced FC between the right vermis and the periaqueductal gray, bilateral culmen and left lingual might reflect a disrupted limbic system. The culmen, congregated in the anterior vermis, might be functionally connected to limbic structures, such as amygdala (Nicholson et al., 2015), hippocampus, nucleus accumbens and orbitofrontal cortex (Lange et al., 2015). Functional hypoconnectivity in anxiety disorders may be characterized by the interruption between the cerebellar nodes involved in the processing of social and aversive stimuli, such as Crus I (Chen et al., 2022), frontal (Yuan et al., 2017) and corticostriatal regions (Zhang et al., 2022). Interestingly, the cerebellar Crus I, shown to be altered in some studies on PTSD and anxiety disorders included herein (e.g., Yin et al., 2011; Yuan et al., 2017, Yuan M. et al., 2018; Rabellino et al., 2018; Nicholson et al., 2020) participates in hippocampus-dependent spatial navigation (e.g., Rondi-Reig et al., 2022) which may be impaired in PTSD (e.g., Smith et al., 2015). Still, further neuroimaging studies are needed to achieve better understanding of potentially altered cerebellum-hippocampus interactions (Watson et al., 2019) in PTSD and anxiety disorders.

Varying structural alterations in the cerebellum have been reported in PTSD (Blithikioti et al., 2022). Baldaçara et al. (2011, 2012) hypothesized that cerebellar hyperactivity might be characterizing the first post-trauma months, and as a consequence of this, cerebellar volume reduction may appear later. Likewise, MRI studies on cerebellar gray matter alterations in anxiety disorders do not provide a coherent picture since increases, decreases as well as null results have been reported even in circumscribed subregions like the vermis (Asami et al., 2009; Cheng et al., 2015; Hilbert et al., 2015). Also, the effects of antidepressant pharmacotherapy on cerebellar GMV have varied in direction (Cassimjee et al., 2010; Talati et al., 2015) which could be related to differences in antidepressant type, treatment duration, MR scanner and absence of control group in one of the studies. Further research aiming at finding sex differences at the cerebellar level could be relevant as sex-dependent results in PD were demonstrated (Asami et al., 2009).

Several limitations of the present mini-review should be considered. Firstly, the included studies differ widely in disorder type, characteristics of the samples, experimental design, intervention, neuroimaging modality, and type of analyses, which could limit the comparability. Small samples in several studies constrain the statistical power (Cremers et al., 2017) and reproducibility of findings (Turner et al., 2018). Moreover, in comparison to regions like the amygdala, only a small fraction of imaging studies has had an explicit cerebellar focus and, anatomically, results are frequently described in broad terms like anterior/posterior or right/left cerebellum, instead of providing a more specific localization (Strata, 2015). Also, the whole cerebellum has not been eligible for analysis in many trials (Fastenrath et al., 2022) as it has been common to remove part of the cerebellum from the field of view of the MR scanner (Anteraper et al., 2022).

In conclusion, this mini-review described and briefly evaluated functional and structural neuroimaging studies reporting on the cerebellum in adult participants with anxiety disorders or PTSD. While the vermis, acting as a limbic node in the cerebellum for emotions, could have a more prominent role in these disorders, it is also evident that the MRI studies evaluated herein report anatomically distributed findings, involving motor as well as non-motor regions of the cerebellum. The functionality of each cerebellar subregion is complex and the consistency and direction of cerebellar involvement across the disorders need further evaluation. To contribute to this, longitudinal and cross-sectional studies and large-scale networks, in combination with the use of ultra-high field MR scans offering improved anatomical precision, could provide a better understanding of the role of the cerebellum in post-traumatic stress and anxiety disorders.

Both authors contributed to the design and conceptualization, literature searching and writing, and approved the final submitted version.