Anatomical, physiological and functional neuroimaging studies suggest that the cerebellum participates in the organization of higher order function, but there are very few descriptions of clinically relevant cases that address this possibility. We performed neurological examinations, bedside mental state tests, neuropsychological studies and anatomical neuroimaging on 20 patients with diseases confined to the cerebellum, and evaluated the nature and severity of the changes in neurological and mental function. Behavioural changes were clinically prominent in patients with lesions involving the posterior lobe of the cerebellum and the vermis, and in some cases they were the most noticeable aspects of the presentation. These changes were characterized by: impairment of executive functions such as planning, set-shifting, verbal fluency, abstract reasoning and working memory; difficulties with spatial cognition including visual-spatial organization and memory; personality change with blunting of affect or disinhibited and inappropriate behaviour; and language deficits including agrammatism and dysprosodia. Lesions of the anterior lobe of the cerebellum produced only minor changes in executive and visual-spatial functions. We have called this newly defined clinical entity the 'cerebellar cognitive affective syndrome'. The constellation of deficits is suggestive of disruption of the cerebellar modulation of neural circuits that link prefrontal, posterior parietal, superior temporal and limbic cortices with the cerebellum.

/pdf/the-cerebellar-cognitive-affective-syndrome-2qlts0j1w1.pdf

The cerebellar cognitive affective syndrome.

The purpose of the present study was to determine whether lesions of areas projected to by the central amygdaloid nucleus (ACE) would disrupt the classical conditioning of autonomic and/or behavioral emotional responses. The areas studied included 3 projection targets of the ACE: the lateral hypothalamic area (LH), midbrain central gray (CG) region, and bed nucleus of the stria terminalis (BNST). Lesions were made either electrolytically or by microinjection of ibotenic acid, which destroys local neurons without interrupting fibers of passage. Two weeks later, the animals were classically conditioned by pairing an acoustic stimulus with footshock. The next day, conditioned changes in autonomic activity (increases in arterial pressure) and emotional behavior ("freezing," or the arrest of somatomotor activity) evoked by the acoustic conditioned stimulus (CS) were measured during extinction trials. Electrolytic and ibotenic acid lesions of the LH interfered with the conditioned arterial pressure response, but did not affect conditioned freezing. Electrolytic lesions of the rostral CG disrupted conditioned freezing but not conditioned changes in arterial pressure. Ibotenic acid injected into the rostral CG reduced neither the arterial pressure nor the freezing response. Injection of ibotenic acid in the caudal CG, like electrolytic lesions of the rostral CG, disrupted the freezing, but not the arterial pressure response. Injection of ibotenic acid into the BNST had no effect on either response. These data demonstrate that neurons in the LH are involved in the autonomic, but not the behavioral, conditioned response pathway, whereas neurons in the caudal CG are involved in the behavioral, but not the autonomic, pathway. Different efferent projections of the central amygdala thus appear to mediate the behavioral and autonomic concomitants of conditioned fear.

https://www.jneurosci.org/content/jneuro/8/7/2517.full.pdf

Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear

Does the cerebellum influence nonmotor behavior? Recent anatomical studies demonstrate that the output of the cerebellum targets multiple nonmotor areas in the prefrontal and posterior parietal cortex, as well as the cortical motor areas. The projections to different cortical areas originate from distinct output channels within the cerebellar nuclei. The cerebral cortical area that is the main target of each output channel is a major source of input to the channel. Thus, a closed-loop circuit represents the major architectural unit of cerebro-cerebellar interactions. The outputs of these loops provide the cerebellum with the anatomical substrate to influence the control of movement and cognition. Neuroimaging and neuropsychological data supply compelling support for this view. The range of tasks associated with cerebellar activation is remarkable and includes tasks designed to assess attention, executive control, language, working memory, learning, pain, emotion, and addiction. These data, along with the revelations about cerebro-cerebellar circuitry, provide a new framework for exploring the contribution of the cerebellum to diverse aspects of behavior.

/pdf/cerebellum-and-nonmotor-function-55lxgbwnri.pdf

Cerebellum and Nonmotor Function

Many diseases involve the cerebellum and produce ataxia, which is characterized by incoordination of balance, gait, extremity and eye movements, and dysarthria. Cerebellar lesions do not always manifest with ataxic motor syndromes, however. The cerebellar cognitive affective syndrome (CCAS) includes impairments in executive, visual-spatial, and linguistic abilities, with affective disturbance ranging from emotional blunting and depression, to disinhibition and psychotic features. The cognitive and psychiatric components of the CCAS, together with the ataxic motor disability of cerebellar disorders, are conceptualized within the dysmetria of thought hypothesis. This concept holds that a universal cerebellar transform facilitates automatic modulation of behavior around a homeostatic baseline, and the behavior being modulated is determined by the specificity of anatomic subcircuits, or loops, within the cerebrocerebellar system. Damage to the cerebellar component of the distributed neural circuit subserving sensorimotor, cognitive, and emotional processing disrupts the universal cerebellar transform, leading to the universal cerebellar impairment affecting the lesioned domain. The universal cerebellar impairment manifests as ataxia when the sensorimotor cerebellum is involved and as the CCAS when pathology is in the lateral hemisphere of the posterior cerebellum (involved in cognitive processing) or in the vermis (limbic cerebellum). Cognitive and emotional disorders may accompany cerebellar diseases or be their principal clinical presentation, and this has significance for the diagnosis and management of patients with cerebellar dysfunction.

https://neuro.psychiatryonline.org/doi/pdfplus/10.1176/jnp.16.3.367

Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome

The cerebellum and cognition.

Electrical stimulation at single sites in the rostral fastigial nucleus elicits hypertension, grooming, feeding, and attack behaviors in the cat. The stimulus intensity and availability of suitable goal objects determines the behavior. Bilateral lesions of the area fail to produce motor deficits. The rostral fastigial nucleus may be a cerebellar area for behavioral and autonomic regulation.

https://science.sciencemag.org/content/sci/182/4114/845.full.pdf

Predatory Attack, Grooming, and Consummatory Behaviors Evoked by Electrical Stimulation of Cat Cerebellar Nuclei

Bilateral electrolytic lesions of the anterior hypothalamus in unrestrained rats resulted in the development, within 2 hours, of arterial hypertension, tachycardia, hyperthermia, and increased locomotor activity, often leading to pulmonary edema and death. Similar lesions in paralyzed, artificially ventilated rats produced comparable changes in arterial blood pressure and body temperature with a similar time course. The arterial hypertension was a consequence of an increase in total peripheral resistance to 15% of control with a reduction in cardiac output to 49% of control. Arterial hypertension, elevated peripheral resistance, and diminished cardiac output were reversed toward normal by alpha-receptor blockade with phentolamine (1 mg/kg, iv). Bilateral adrenalectomy, adrenal demedullation, or adrenal denervation performed prior to lesion placement prevented the development of arterial hypertension and pulmonary edema as well as the changes in peripheral resistance, cardiac output, and body temperature. We conclude that arterial hypertension following lesions of the anterior hypothalamus is due to a neurally mediated increase in peripheral resistance initiated by the release of adrenal medullary catecholamines and that pulmonary edema is due to myocardial failure secondary to the ensuing ventricular overload. Structures originating in or passing through the anterior hypothalamus may exert selective control over the adrenal medulla independent of vasomotor neurons.

Fulminating arterial hypertension with pulmonary edema from release of adrenomedullary catecholamines after lesions of the anterior hypothalamus in the rat

The effects of selective destruction of the catecholamine innervation of the nucleus tractus solitarii (NTS) on arterial pressure (MAP) and heart rate (HR) were examined in unanesthetized rats in which 6-hydroxydopamine (6-OHDA), 1μl, was injected bilaterally into the nucleus at the level of the obex. Control rats received 1 fil of vehicle or were uninjected. Baroreceptor reflex activity was tested by measuring the reflex bradycardia in response to graded doses of phenylephrine. 6-OHDA, 2 μg, did not alter MAP or HR; 12 μg, a dose producing necrosis of NTS, resulted in the development within 4-6 hours of fulminating arterial hypertension and tachycardia. 6-OHDA, 4 fig, produced an elevation of MAP which returned to control levels by 48 hours without changing HR. By 6 hours, however, the arterial pressure became extremely labile. Lability of MAP in the absence of hypertension or change of HR persisted for the longest period of observation, 2 weeks. Baroreceptor reflex activity remained, although the sensitivity of the reflex was depressed. 6-OHDA, 4 μg, failed to produce histological damage to NTS. Biochemically, it resulted after 14 days in a reduction of the activity of dopamine β-hydroxylase, a specific marker of noradrenergic and adrenergic neurons, to 40% of control without altering the activity of choline acetyltransferase, a marker of cholinergic neurons. We conclude that selective removal of a substantial portion of the catecholamine innervation of the NTS, mostly noradrenergic, results in persistent lability without elevation of arterial pressure. The results suggest that the catecholamine innervation of NTS modulates rather than mediates baroreceptor reflexes, serving to maintain arterial pressure within narrow limits.

Chronic lability of arterial pressure produced by selective destruction of the catecholamine innervation of the nucleus tractus solitarii in the rat.

Publisher Summary This chapter attempts to produce experimental neurogenic-hypertension in laboratory animals by electrolytic and chemical lesions of the brain It demonstrates that it is possible to produce chronic hypertension by lesions of nucleus of the tractus solitarii (NTS), thereby validating the hypothesis that central neural imbalances can result in hypertension The chapter also presents the studies demonstrating that selective destruction of the noradrenergic innervation of NTS by the drug 6-hydroxydopamine (6-OHDA), which selectively destroys noradrenergic terminals, can result in the development of marked lability of the arterial pressure This would suggest that the defects of chemical neurotransmission within the central nervous system (CNS) could possibly contribute to the conditions favoring the development of hypertension It is concluded that chronic neurogenic hypertension can result from imbalances in the CNS that result in disinhibition of sympathetic vasomotor outflow Specific biochemical defects of neurotransmitter systems, particularly of the noradrenergic innervation of the NTS, could possibly lead over time to the development of hypertension

Brain lesions and hypertension: chronic lability and elevation of arterial pressure produced by electrolytic lesions and 6-hydroxydopamine treatment of nucleus tractus solitarii (NTS) in rat and cat.

Cats were classically conditioned after the baroreceptor reflexes were abolished by bilateral placement of electrolytic lesions in the nucleus tractus solitarii. The conditioned increases in arterial pressure were more than five times larger than the responses obtained in similarly trained controls. This finding suggests that the baroreceptor reflexes actively inhibit conditioned increases of arterial pressure.

Marc A. Nathan

Papers

Predatory Attack, Grooming, and Consummatory Behaviors Evoked by Electrical Stimulation of Cat Cerebellar Nuclei

Fulminating arterial hypertension with pulmonary edema from release of adrenomedullary catecholamines after lesions of the anterior hypothalamus in the rat

Chronic lability of arterial pressure produced by selective destruction of the catecholamine innervation of the nucleus tractus solitarii in the rat.

Brain lesions and hypertension: chronic lability and elevation of arterial pressure produced by electrolytic lesions and 6-hydroxydopamine treatment of nucleus tractus solitarii (NTS) in rat and cat.

Enhancement of Conditioned Arterial Pressure Responses in Cats After Brainstem Lesions