The neuropathological basis of anxiety in Parkinson’s disease

Evidence suggests that 24.5%–46.7% (mean 31%) of patients with Parkinson’s disease experience an anxiety disorder, a much higher prevalence than in controls. Anxiety does not appear to be a consequence of diagnosis or the motoric symptoms of the disorder and can manifest as Generalised Anxiety Disorder, phobias or panic attacks. At present, the neural underpinnings of anxiety disorders in Parkinson’s disease is unknown. Here, we make the novel proposal that the superior colliculus (SC), one component of a rapid, reflexive threat detection system in the brain, consisting of the colliculus, pulvinar and amygdala, becomes hyper-responsive to sensory stimuli following dopamine denervation of the striatum in Parkinson’s disease. This in turn leads to heightened responses to existing threat-related stimuli (giving rise to phobias and panic attacks), and heightened responses to anticipated threats (giving rise to Generalised Anxiety Disorder). This proposal is supported by a range of evidence, in particular elevated visual responses in the SC in an animal model of Parkinson’s disease and in Parkinson’s disease itself. Also facilitated saccadic eye movements (prosaccades, express saccades and fixational saccades) and increased distractibility in Parkinson’s disease, both of which involve the SC. Identifying one potential locus of change in the brain in Parkinson’s disease relevant to anxiety gives a potential target for interventions to combat a non-motor symptom that has a substantial negative effect on quality of life in the disorder

Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease

Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinson's disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinson's disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action. © 2010 Macmillan Publishers Limited. All rights reserved

D-amphetamine depresses visual responses in the rat superior colliculus: a possible mechanism for amphetamine-induced decreases in distractibility.

International audienceAmphetamines can enhance sustained attention, and reduce distractibility, in normal subjects and patients with attentional-deficit/hyperactivity disorder (ADHD). Their mechanism of action in this regard is unknown, however one possibility is that the drugs affect the superior colliculus (SC), a structure with a clearly defined role in distractibility. The aim of the present studies was to explore the effect of systemically and locally administered d-amphetamine on visual responses in the superficial layers of the SC to wholefield light flashes in the rat, using local field potential and multi-unit recording. Systemic and intra-collicular d-amphetamine both produced a dose-related depression of visual activity, which sometimes progressed to inactivation of the multi-unit response at the highest dose. As a consequence, it is possible that amphetamines enhance sustained attention, and reduce distractibility, via an action on the colliculus. A corollary of this is that collicular dysfunction may underlie enhanced distractibility in ADHD

Separation of channels subserving approach and avoidance/escape at the level of the basal ganglia and related brainstem structures

The basal ganglia have a key function of directing our behavior in the context of events from our environment and/or our internal state. This function relies on afferents targeting the main input structures of the basal ganglia, entering bids for action selection at the level of the striatum, or signals for behavioral interruption at the level of the subthalamic nucleus, with behavioral reselection facilitated by dopamine signaling. Numerous experiments have studied action selection in relation to inputs from the cerebral cortex, however less is known about the anatomical and functional link between the basal ganglia and the brainstem. In this review, we describe how brainstem structures also project to the main input structures of the basal ganglia, namely the striatum, the subthalamic nucleus and midbrain dopaminergic neurons, in the context of approach and avoidance (including escape from threat), two fundamental, mutually exclusive behavioral choices in an animal’s repertoire in which the brainstem is strongly involved. We focus on three particularly well described loci involved in approach and avoidance, namely the superior colliculus, the parabrachial nucleus and the periaqueductal grey nucleus. We consider what is known about how these structures are related to the basal ganglia, focusing on their projections toward the striatum, dopaminergic neurons and subthalamic nucleus, and explore the functional consequences of those interactions

The subthalamic nucleus: a hub for sensory control via short three-lateral loop connections with the brainstem?

The subthalamic nucleus (STN) is classically subdivided into sensori-motor, associative and limbic regions which is consistent with the involvement of this structure in motor control, but also in cognitive and emotional tasks. However, the function of the sensory inputs to the STN’s sensori-motor territory is comparatively less well explored, although sensory responses have been reported in this structure. There is still a paucity of information regarding the characteristics of that subdivision and its potential functional role in the basal ganglia processing and more widely in associated networks. In this Perspective paper, we summarize the type of sensory stimuli that have been reported to activate the STN, describe the complex sensory properties of the STN and its anatomical link to a sensory network involving the brainstem, characterized in our recent work. Analyzing the sensory input to the STN led us to suggest the existence of previously unreported three-lateral subcortical loops between the basal ganglia and the brainstem which do not involve the cortex. Anatomically, these loops closely link the STN, the substantia nigra pars reticulata and various structure from the brainstem such as the superior colliculus and the parabrachial nucleus. We also discuss the potential role of the STN in the control of sensory activity in the brainstem and its possible contribution to favoring sensory habituation or sensitization over brainstem structures to optimize the best selection of action at a given time

Altered parabrachial nucleus nociceptive processing may underlie central pain in Parkinson’s disease.

The presence of central neuropathic pain in Parkinson’s disease suggests that the brain circuits that allow us to process pain could be dysfunctional in the disorder. However, there is to date no clear pathophysiological mechanism to explain these symptoms. In this work, we present evidence that the dysfunction of the subthalamic nucleus and/or substantia nigra pars reticulata may impact nociceptive processing in the parabrachial nucleus (PBN), a low level primary nociceptive structure in the brainstem, and induce a cellular and molecular neuro-adaptation in this structure. In rat models of Parkinson’s disease with a partial dopaminergic lesion in the substantia nigra compacta, we found that the substantia nigra reticulata showed enhanced nociceptive responses. Such responses were less impacted in the subthalamic nucleus. A total dopaminergic lesion produced an increase in the nociceptive responses as well as an increase of the firing rate in both structures. In the PBN, inhibited nociceptive responses and increased expression of GABAA receptors were found following a total dopaminergic lesion. However, neuro-adaptations at the level of dendritic spine density and post-synaptic density were found in both dopaminergic lesion groups. These results suggest that the molecular changes within the PBN following a larger dopaminergic lesion, such as increased GABAA expression, is a key mechanism to produce nociceptive processing impairment, whilst other changes may protect function after smaller dopaminergic lesions. We also propose that these neuro-adaptations follow increased inhibitory tone from the substantia nigra pars reticulata and may represent the mechanism generating central neuropathic pain in Parkinson’s disease

Short-latency visual input to the subthalamic nucleus is provided by the midbrain superior colliculus.

The subthalamic nucleus (STN) is one of the principal input nuclei of the basal ganglia. Using electrophysiological techniques in anesthetized rats, we show that the STN becomes responsive to visual stimuli at short latencies when local disinhibitory injections are made into the midbrain superior colliculus (SC), an important subcortical visual structure. Significantly, only injections into the lateral, but not medial, deep layers of the SC were effective. Corresponding disinhibition of primary visual cortex also was ineffective. Complementary anatomical analyses revealed a strong, regionally specific projection from the deep layers of the lateral SC to neurons in rostral and dorsal sectors of the STN. Given the retinocentric organization of the SC, these results suggest that lower-field stimuli represented in the lateral colliculus have a direct means of communicating with the basal ganglia via the STN that is not afforded to visual events occurring in the upper visual field

The parabrachial nucleus is a critical link in the transmission of short latency nociceptive information to midbrain dopaminergic neurons

Many dopaminergic neurons exhibit a short-latency response to noxious stimuli, the source of which is unknown. Here we report that the nociceptive-recipient parabrachial nucleus appears to be a critical link in the transmission of pain related information to dopaminergic neurons. Injections of retrograde tracer into the substantia nigra pars compacta of the rat labelled neurons in both the lateral and medial parts of the parabrachial nucleus, and intra-parabrachial injections of anterograde tracers revealed robust projections to the pars compacta and ventral tegmental area. Axonal boutons were seen in close association with tyrosine hydroxylase-positive (presumed dopaminergic) and negative elements in these regions. Simultaneous extracellular recordings were made from parabrachial and dopaminergic neurons in the anaesthetized rat, during the application of noxious footshock. Parabrachial neurons exhibited a short-latency, short duration excitation to footshock while dopaminergic neurons exhibited a short-latency inhibition. Response latencies of dopaminergic neurons were reliably longer than those of parabrachial neurons. Intra-parabrachial injections of the local anasethetic lidocaine or the GABAA receptor antagonist muscimol reduced tonic parabrachial activity and the amplitude (and in the case of lidocaine, duration) of the phasic response to footshock. Suppression of parabrachial activity with lidocaine reduced the baseline firing rate of dopaminergic neurons, while both lidocaine and muscimol reduced the amplitude of the phasic inhibitory response to footshock, in the case of lidocaine sometimes abolishing it altogether. Considered together, these results suggest that the parabrachial nucleus is an important source of short-latency nociceptive input to the dopaminergic neurons