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Cerebellar Connections with Limbic Circuits: Anatomy and Functional Implications
Abstract
There is an emerging body of evidence suggesting that the cerebellum participates in limbic-related functions including emotion and affect. The underlying connectivity of the cerebellar cortex and nuclei with limbic-related brain areas and associative and paralimbic cortices suggests widespread cerebellar influence on behaviors including the experience and expression of emotion, sadness and grief, integrative hypothalamic visceral/sensory functions, pain perception, modulation, and intensity due to noxious stimuli, as well as other nonmotor behaviors. The key anatomical relationships are the fastigial nucleus projections to the ventral tegmental area (VTA), cerebellar interconnections with the septum, hippocampus and amygdala, direct cerebellar connections with hypothalamic circuits that integrate somatic-, visceral-, and limbic-related activity, and indirect connections with the nucleus accumbens (NAcc), a mesolimbic dopaminergic structure that predicts activity in a reward paradigm in limbic-related structures. Additionally, the cerebellum is interconnected with cingulate cortices that play a role in motivation and emotional drive, and with associative and paralimbic regions of prefrontal, posterior parietal, superior temporal polymodal, and parahippocampal regions heavily implicated in high order processing important for the integration of cognition and emotion. These connections between cortical and subcortical areas of the limbic system with the cerebellum (vermis and fastigial nucleus in particular) are the likely anatomical underpinning of the demonstrated cerebellar influence on limbic-related behaviors in the clinical setting and in earlier behavioral and physiological studies. These cerebellar connections with cerebral limbic areas are also implicated in neurodevelopmental disorders such as autism which demonstrate neuropathology and aberrant neurochemistry in the cerebellar cortex and nuclei. Defining the vermis and fastigial nuclei as the probable location of the limbic cerebellum has relevance for future studies of cerebrocerebellar interconnections and functional coupling, and for therapeutic strategies that attempt to enhance cerebellar modulation of limbic-related structures in order to treat neuropsychiatric disorders.
... The Cbm, anatomically linked to the above-mentioned structures, is notoriously involved in emotional processing [23]. Perception is processed by the thalamic-cortical circuits whose psychological and emotional implications are the result of the activity of the limbic system (LS) [23]. ...
... The Cbm, anatomically linked to the above-mentioned structures, is notoriously involved in emotional processing [23]. Perception is processed by the thalamic-cortical circuits whose psychological and emotional implications are the result of the activity of the limbic system (LS) [23]. ...
... In this regard, an interesting compartmentalization has been found: the cognitive symptoms develop in case of lesions mainly in the posterior lobe of the Cbm [44,45], while the affective ones show themselves in associations to damage on the vermis [23,40,46]. ...
Major Depressive Disorder (MDD) and Bipolar Disorder (BD) are the most frequent mental disorders whose indeterminate etiopathogenesis spurs to explore new aetiologic scenarios. In light of the neuropsychiatric symptoms characterizing Cerebellar Cognitive Affective Syndrome (CCAS), the objective of this narrative review is to analyze the involvement of the cerebellum (Cbm) in the onset of these conditions. It aims at detecting the repercussions of the Cbm activities on mood disorders based on its functional subdivision in vestibulocerebellum (vCbm), pontocerebellum (pCbm) and spinocerebellum (sCbm). Despite the Cbm having been, for decades, associated with somato-motor functions, the described intercellular pathways, without forgiving the molecular impairment and the alteration in the volumetric relationships, make the Cbm a new important therapeutic target for MDD and BD. Given that numerous studies have showed its activation during mnestic activities and socio-emotional events, this review highlights in the Cbm, in which the altered external space perception (vCbm) is strictly linked to the cognitive-limbic Cbm (pCbm and sCbm), a crucial role in the MDD and BD pathogenesis. Finally, by the analysis of the cerebellar activity, this study aims at underlying not only the Cbm involvement in affective disorders, but also its role in social relationship building.
... LC axons also project to the cerebellum (CB) 17,18 , a brain region implicated in emotional associative learning [19][20][21] via its outputs to the amygdala, periaqueductal gray, hypothalamus and pre-frontal cortex [22][23][24] . Notably, stimulation of the CB vermis produces freezing and bradycardia, whereas lesions of the vermis (lobules IV and V) inhibit autonomic and behavioral fear responses [25][26][27][28] . ...
The modulation of dopamine release from midbrain projections to the striatum has long been demonstrated in reward-based learning, but the synaptic basis of aversive learning is far less characterized. The cerebellum receives axonal projections from the locus coeruleus, and norepinephrine release is implicated in states of arousal and stress, but whether aversive learning relies on plastic changes in norepinephrine release in the cerebellum is unknown. Here we report that in mice, norepinephrine is released in the cerebellum following an unpredicted noxious event (a foot-shock) and that this norepinephrine release is potentiated powerfully with fear acquisition as animals learn that a previously neutral stimulus (tone) predicts the aversive event. Importantly, both chemogenetic and optogenetic inhibition of the locus coeruleus-cerebellum pathway block fear memory without impairing motor function. Thus, norepinephrine release in the cerebellum is modulated by experience and underlies aversive learning.
... Anatomical and physiological studies have shown that the midline cerebellar vermis is particularly involved in emotional processing and that lesions and other interventions on this cerebellar compartment affect emotion-related behaviors (reviewed in Apps et al., 2018). The cerebellar vermis receives olivocerebellar (CF) input from the caudal medial accessory olive and emits a cortico-nuclear output to the medial (fastigial) cerebellar nucleus which, in turn, has widespread projections to the cingulate cortex, prefrontal cortex, parietal cortex, amygdala, hypothalamus, hippocampus, periaqueductal gray (PAG), and striatum (Voogd and Ruigrok, 2004;Blatt et al., 2013;Rolls, 2019) (see also next chapter). ...
The cerebellum operates exploiting a complex modular organization and a unified computational algorithm adapted to different behavioral contexts. Recent observations suggest that the cerebellum is involved not just in motor but also in emotional and cognitive processing. It is therefore critical to identify the specific regional connectivity and microcircuit properties of the emotional cerebellum. Recent studies are highlighting the differential regional localization of genes, molecules, and synaptic mechanisms and microcircuit wiring. However, the impact of these regional differences is not fully understood and will require experimental investigation and computational modeling. This review focuses on the cellular and circuit underpinnings of the cerebellar role in emotion. And since emotion involves an integration of cognitive, somatomotor, and autonomic activity, we elaborate on the tradeoff between segregation and distribution of these three main functions in the cerebellum.
... The absence of de novo cognitive impairments and the absence of a CCAS in our patient is in full accord with the current conception of the topical organization of the cerebellum [45,47]. According to this conception, which is supported by an impressive body of evidence [45][46][47][48][49][50], the anterior vermis subserves motor control in the lower limbs and also subserves emotion (it is the "limbic cerebellum", according to Schmahmann [93]). Our patient showed emotional instability, which appears to continue up until today, but it is difficult to decide whether this is best explained through her difficult circumstances or through anterior vermis damage. ...
Background:
Alcoholic cerebellar degeneration is a restricted form of cerebellar degeneration, clinically leading to an ataxia of stance and gait and occurring in the context of alcohol misuse in combination with malnutrition and thiamine depletion. However, a similar degeneration may also develop after non-alcoholic malnutrition, but evidence for a lasting ataxia of stance and gait and lasting abnormalities in the cerebellum is lacking in the few patients described with purely nutritional cerebellar degeneration (NCD).
Methods:
We present a case of a 46-year-old woman who developed NCD and Wernicke's encephalopathy (WE) due to COVID-19 and protracted vomiting, resulting in thiamine depletion. We present her clinical course over the first 6 months after the diagnosis of NCD and WE, with thorough neuropsychological and neurological examinations, standardized clinical observations, laboratory investigations, and repeated MRIs.
Results:
We found a persistent ataxia of stance and gait and evidence for an irreversible restricted cerebellar degeneration. However, the initial cognitive impairments resolved.
Conclusions:
Our study shows that NCD without involvement of alcohol neurotoxicity and with a characteristic ataxia of stance and gait exists and may be irreversible. We did not find any evidence for lasting cognitive abnormalities or a cerebellar cognitive-affective syndrome (CCAS) in this patient.
... The cerebellar vermis is known as the "limbic cerebellum" because of its numerous anatomical connections to the rest of the limbic system (Blatt et al., 2013;Reeber et al., 2013). These include brain regions that are known to mediate anxiety, such as the periaqueductal gray (PAG; Snider and Maiti, 1976) and dorsal raphe nuclei (DRN; Pierce et al., 1977). ...
Although the cerebellum is traditionally known for its role in motor functions, recent evidence points toward the additional involvement of the cerebellum in an array of non-motor functions. One such non-motor function is anxiety behavior: a series of recent studies now implicate the cerebellum in anxiety. Here, we review evidence regarding the possible role of the cerebellum in anxiety—ranging from clinical studies to experimental manipulation of neural activity—that collectively points toward a role for the cerebellum, and possibly a specific topographical locus within the cerebellum, as one of the orchestrators of anxiety responses.
... Some researchers have detected cerebellar activation during narrative processing (Xu et al., 2005;AbdulSabur et al., 2014) and during the integration of narrative (movie) events into coherent event sequences (Lahnakoski et al., 2017). Importantly, areas that are involved in narrative production (Mar, 2004) are also connected to the cerebellum (Blatt et al., 2013;Watson et al., 2014;Palesi et al., 2017). Overand underconnectivity between these areas has been observed in autism (Khan et al., 2015;Igelström et al., 2017;Olivito et al., 2018). ...
Adults diagnosed with autism experience difficulties with understanding the mental states of others, or themselves (mentalizing) and with adequately sequencing personal stories (narrative coherence). Given that the posterior cerebellum is implicated in both skills, as well as in the etiology of autism, we developed a narrative sequencing and mentalizing training for autistic adults. Participants with an official autism diagnosis were randomly assigned to a Training group (n = 17) or a waiting-list Control group (n = 15). The Training group took part in six weekly sessions in groups of three participants lasting each about 60 min. During training, participants had to (re)tell stories from the perspective of the original storyteller and answer questions that required mentalizing. We found significant improvements in mentalizing about others’ beliefs and in narrative coherence for the Training group compared to the Control group immediately after the training compared to before the training. Almost all participants from the Training group expressed beneficial effects of the training on their mood and half of the participants reported positive effects on their self-confidence in social situations. All participants recommended the current training to others. Results are discussed in light of cerebellar theories on sequencing of social actions during mentalizing. Further improvements to the program are suggested. Our results highlight the potential clinical utility of adopting a neuroscience-informed approach to developing novel therapeutic interventions for autistic populations.
... Participation of the cerebellum in basic emotional responses became considerable after multiple cerebellar-limbic connections had been found [48]. The specific impact of cerebellar activity on the autonomic nervous system (ANS) functioning was also observed. ...
The cerebellum is a well-established primary brain center in charge of controlling sensorimotor functions and non-motor functions. Recent reports depicted the significance of cerebellum in higher-order cognitive functions including emotion-processing, language, reward-related behavior, working memory, and social behavior. As it can influence diverse behavioral patterns, any defects in cerebellar functions could invoke neuropsychiatric diseases as indicated by the incidence of alexithymia and induce alterations in emotional and behavioral patterns. Furthermore, its defects can trigger motor diseases, such as ataxia and Parkinson’s disease (PD). In this review, we have extensively discussed the role of cerebellum in motor and non-motor functions and how the cerebellum malfunctions in relation to the neural circuit wiring as it could impact brain function and behavioral outcomes in the patients with neuropsychiatric diseases. Relevant data regarding cerebellar non-motor functions have been vividly described along with anatomy and physiology of these functions. In addition to the defects in basal ganglia, the lack of activity in motor related regions of the cerebellum could be associated with the severity of motor symptoms. All together, this review delineates the importance of cerebellar involvement in patients with PD and unravels a crucial link for various clinical aspects of PD with specific cerebellar sub-regions.
Role of fear in COVID-19
Background
Little is known about the effects of social exclusion on youth with bipolar disorder (BD). Understanding these effects and the functional neural correlates of social exclusion in youth with BD may establish differences from healthy youth and help identify areas of intervention.
Methods
We investigated brain function in 19 youth with BD and 14 age and gender matched healthy control (HC) participants while performing Cyberball, an fMRI social exclusion task. Whole brain activation, region-of-interest, and functional connectivity were compared between groups and examined with behavioral measures.
Results
Compared with the HC group, youth with BD exhibited greater activation in the left fusiform gyrus (FFG) during social exclusion. Functional connectivity between the left FFG and the posterior cingulate/precuneus was significantly greater in the HC compared with the BD group. For the HC group only, age and subjective distress during Cyberball significantly predicted mean FFG activation. No significant differences in distress during social exclusion were found between groups.
Conclusion
Although preliminary due to small sample size, these data suggest that youth with BD process social exclusion in a manner that focuses on basic visual information while healthy youth make use of past experiences to interpret current social encounters. This difference may account for the social cognitive issues experienced by youth with BD, which can lead to more severe anxiety and mood symptoms.
Transient global amnesia (TGA) consists of acute-onset anterograde amnesia and typically resolves within 24 hours. Reported etiologies of TGA include transient ischemia to the hippocampus or thalamus, migraine, venous flow abnormalities, and epilepsy. There are no reports of cerebellar ischemia as an etiology of TGA. A 78-year-old woman with a medical history of diabetes presented to the Ohio State University ER after a period of anterograde amnesia lasting 3 hours. She was alert during the event, but asked the same questions repeatedly. Upon arrival to the ER, she was hypertensive but clinically back to baseline, with no recall of the 3-hour time period. An MRI of her brain revealed an isolated hyperintense signal on diffusion-weighted imaging (DWI) at the junction of the superior cerebellum and vermis, with apparent diffusion coefficient correlation. Vascular imaging of the brain and neck and a routine EEG were unremarkable. We diagnosed her with cerebellar ischemia presenting as TGA. She had no head injury, migraine, or history of epilepsy to suggest alternative etiologies of TGA. An increasing amount of literature has reported that the cerebellum is linked to the limbic system. A case series of SPECT imaging on individuals with TGA revealed transient cerebellar vermis hypoperfusion in addition to hippocampal DWI changes. We present what may be a novel report of isolated cerebellar ischemia presenting as TGA, and we add to the literature for clinicians to consider the possibility that damage to the cerebellum or its circuit to the cerebrum or thalamus can present as TGA.
The cerebellum is known to project via the thalamus to multiple motor areas of the cerebral cortex. In this study, we examined the extent and anatomical organization of cerebellar input to multiple regions of prefrontal cortex. We first used conventional retrograde tracers to map the origin of thalamic projections to five prefrontal regions: medial area 9 (9m), lateral area 9 (9l), dorsal area 46 (46d), ventral area 46, and lateral area 12. Only areas 46d, 9m, and 9l received substantial input from thalamic regions included within the zone of termination of cerebellar efferents. This suggested that these cortical areas were the target of cerebellar output. We tested this possibility using retrograde transneuronal transport of the McIntyre-B strain of herpes simplex virus type 1 from areas of prefrontal cortex. Neurons labeled by retrograde transneuronal transport of virus were found in the dentate nucleus only after injections into areas 46d, 9m, and 9l. The precise location of labeled neurons in the dentate varied with the prefrontal area injected. In addition, the dentate neurons labeled after virus injections into prefrontal areas were located in regions spatially separate from those labeled after virus injections into motor areas of the cerebral cortex. Our observations indicate that the cerebellum influences several areas of prefrontal cortex via the thalamus. Furthermore, separate output channels exist in the dentate to influence motor and cognitive operations. These results provide an anatomical substrate for the cerebellum to be involved in cognitive functions such as planning, working memory, and rule-based learning.
Neuroimaging studies report cerebellar activation during both motor and non-motor paradigms, and suggest a functional topography within the cerebellum. Sensorimotor tasks activate the anterior lobe, parts of lobule VI, and lobule VIII, whereas higher-level tasks activate lobules VI and VII in the posterior lobe. To determine whether these activation patterns are evident at a single-subject level, we conducted functional magnetic resonance imaging (fMRI) during five tasks investigating sensorimotor (finger tapping), language (verb generation), spatial (mental rotation), working memory (N-back), and emotional processing (viewing images from the International Affective Picture System). Finger tapping activated the ipsilateral anterior lobe (lobules IV-V) as well as lobules VI and VIII. Activation during verb generation was found in right lobules VII and VIIIA. Mental rotation activated left-lateralized clusters in lobules VII-VIIIA, VI-Crus I, and midline VIIAt. The N-back task showed bilateral activation in right lobules VI-Crus I and left lobules VIIB-VIIIA. Cerebellar activation was evident bilaterally in lobule VI while viewing arousing vs. neutral images. This fMRI study provides the first proof of principle demonstration that there is topographic organization of motor execution vs. cognitive/emotional domains within the cerebellum of a single individual, likely reflecting the anatomical specificity of cerebro-cerebellar circuits underlying different task domains. Inter-subject variability of motor and non-motor topography remains to be determined.
Air hunger (uncomfortable urge to breathe) is a component of dyspnea (shortness of breath). Three human H 2 ¹⁵ O positron emission tomography (PET) studies have identified activation of phylogenetically ancient structures in limbic and paralimbic regions during dyspnea. Other studies have shown activation of these structures during other sensations that alert the organism to urgent homeostatic imbalance: pain, thirst, and hunger for food. We employed blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to examine activation during air hunger. fMRI conferred several advantages over PET: enhanced signal-to-noise, greater spatial resolution, and lack of ionizing radiation, enabling a greater number of trials in each subject. Six healthy men and women were mechanically ventilated at 12–14 breaths/min. The primary experiment was conducted at mean end-tidal Pco 2 of 41 Torr. Moderate to severe air hunger was evoked during 42-s epochs of lower tidal volume (mean = 0.75 L). Subjects described the sensation as “like breath-hold,” “urge to breathe,” and “starved for air.” In the baseline condition, air hunger was consistently relieved by epochs of higher tidal volume (mean = 1.47 L). A control experiment in the same subjects under a background of mild hypocapnia (mean end-tidal PCO 2 = 33 Torr) employed similar tidal volumes but did not evoke air hunger, controlling for stimulus variables not related to dyspnea. During each experiment, we maintained constant end-tidal Pco 2 and PO 2 to avoid systematic changes in global cerebral blood flow. Whole-brain images were acquired every 5 s (T2*, 56 slices, voxel resolution 3 × 3 × 3 mm). Activations associated with air hunger were determined using voxel-based interaction analysis of covariance that compared data between primary and control experiments (SPM99). We detected activations not seen in the earlier PET study using a similar air hunger stimulus ( Banzett et al. 2000 ). Limbic and paralimbic loci activated in the present study were within anterior insula (seen in all 3 published studies of dyspnea), anterior cingulate, operculum, cerebellum, amygdala, thalamus, and basal ganglia. Elements of frontoparietal attentional networks were also identified. The consistency of anterior insular activation across subjects in this study and across published studies suggests that the insula is essential to dyspnea perception, although present data suggest that the insula acts in concert with a larger neural network.
This book presents the anatomical systems that take part in the scientific and clinical study of emotional functions and neuropsychiatric disorders. It discusses the limbic system (the cortical and subcortical structures in the human brain involved in emotion, motivation, and emotional association with memory) at length and how this is no longer a useful guide to the study of psychiatric disorders. The book provides an understanding of brain anatomy, with an emphasis on the new anatomical framework which has emerged during the last quarter century. The goal is to provide the reader will develop an understanding of the gross anatomical organisation of the human forebrain. 1) The book provides an understanding of brain anatomy, with an emphasis on the new anatomical framework which has emerged during the last quarter century 2) The reader will develop an understanding of the gross anatomical organisation of the human forebrain 3) The origin and meaning of terms such as ventral stiatum, ventral pallidum and cortico-subcorticalreentrant circuits, which are increasingly familiar terms in basic and clinical neuroscience, are discussed 4) The extended amygdala and its place in the functional-anatomical organisation of the brain, is discussed 5) The greater limbic lobe and its particular relevance in neuropsyciatric disorders, is presented 6) The role of functional neurosurgery in the treatment of neuropsychiatric disorders is presented 7) The challenges that lie ahead in the field of deep brain stimulation are discussed 8) The book included 2 dvd's of brain dissection, particularly useful for the course instructor.
Although the relationship between limbic system structures and emotionality is well known, the role of the cerebellum in the control of affective behavior is not usually appreciated (Berman, 1970a, b; 1971). Involvement of the limbic system in the elaboration of emotional behavior has been demonstrated by studies such as those of Kluver and Bucy (1939), Pribram and Bagshaw (1953) and Weiskrantz (1956), in which a taming effect was reported following amygdaloidectomy in the monkey. Reduced emotionality in the monkey has also been reported following cingulectomy (Glees, Cole, Whitty, & Cairns, 1950) and postero-medial orbital frontal cortex ablations (Butter, Snyder, & McDonald, 1970).