Zona incerta as a therapeutic target in Parkinson’s disease

Ossowska, Krystyna

doi:10.1007/s00415-019-09486-8

Cited by 51 publications

(33 citation statements)

References 146 publications

(416 reference statements)

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“…We also observed labeling outside the ventral nuclei, including the thalamic reticular nucleus (TRN), two association nuclei (lateral posterior, LP and mediodorsal, MD), primary relay nuclei (LGN and MGN), and zona incerta (ZI) (Ossowska, 2020). MD is engaged during reversal learning (Mitchell and Chakraborty, 2013), sends its output to frontal regions (Hunnicutt et al, 2014), and is engaged in cognitive and working memory tasks in humans (Mitchell and Chakraborty, 2013).…”

Section: The Cerebellum Sends Output To a Wide Range Of Thalamic Targetsmentioning

confidence: 84%

Homologous organization of cerebellar pathways to sensory, motor, and associative forebrain

Pisano

Dhanerawala

Kislin

et al. 2020

Preprint

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16Cerebellar outputs take multisynaptic paths to reach higher brain areas, impeding tracing 17 efforts. Here we quantify pathways between cerebellum and contralateral 18 thalamic/corticostriatal structures using the anterograde transsynaptic tracer herpes 19 simplex virus type 1 (H129), the retrograde tracer pseudorabies virus (Bartha), adeno-20 associated virus, and a whole-brain pipeline for neuron-level analysis using light-sheet 21 microscopy. In ascending pathways, sensorimotor regions contained the most labeled 22 neurons, but higher densities were found in associative areas, including orbital, anterior 23 cingulate, prelimbic, and infralimbic cortex. Ascending paths passed through most 24 thalamic nuclei, especially ventral posteromedial and lateral posterior (sensorimotor), 25 mediodorsal (associative), and reticular (modulatory) nuclei. Retrograde tracing revealed 26 descending paths originating largely from somatomotor cortex. Patterns of ascending 27 influence correlated with anatomical pathway strengths, as measured by brainwide 28 mapping of c-Fos responses to optogenetic inhibition of Purkinje cells. Our results 29 reveal parallel functional networks linking cerebellum to forebrain and suggest that 30 cerebellum uses sensory-motor information to guide both movement and nonmotor 31 functions. 32 most mammalian brains 8 . The major descending corticocerebellar pathway passes through the 41 pons and the majority of returning ascending fibers pass through the thalamus 9,10 , comprising 42 two massive within-brain long-distance pathways 11 . Other polysynaptic pathways exist between 43 the cerebellum and neocortex, including a smaller ascending pathway through ventral tegmental 44 area that has attracted recent interest 12 . These descending and ascending pathways are 45 suggested to form closed loops 13 , giving each cerebellar region one or more specific neocortical 46 partners with which it exchanges information. 47This picture lacks critical information: the identity of those distant regions, which have 48 been difficult to map. Given the brain-wide nature of cerebello-cortical pathways, researchers 49 have used large-scale approaches to examine the functional significance of these pathways. 50Transcranial magnetic stimulation in humans demonstrated that the cerebellum influences 51 neocortical excitability 14 , including cognitive and affective circuits 15 . Functional MRI can attain 52 subcentimeter resolution, detect long-distance correlations 16 , and when coupled with cerebellar 53 stimulation, demonstrate causal relationships 17 . Functional imaging at cellular resolution in 54 nonhuman animals has been made possible by visualizing c-Fos, an immediate-early gene 55 product whose expression is regulated by neural activity. Although useful in demonstrating 56 communication with distant brain regions, these methods do not provide cellular-resolution 57 information about cerebello-cortical circuits. 58Pathways entering and exiting the cerebellum pass through synapses in the brainstem 59 and the cer...

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Section: The Cerebellum Sends Output To a Wide Range Of Thalamic Targetsmentioning

confidence: 84%

Homologous organization of cerebellar pathways to sensory, motor, and associative forebrain

Pisano

Dhanerawala

Kislin

et al. 2020

Preprint

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“…Previous work in ZI has shown chemoarchitectural diversity among the four ZI sectors and differences in interconnections with the basal ganglia network (see reviews: (12,17)). Rostral ZI can be differentiated from others through dopaminergic neurons (A13 region) and interconnections with the cerebral cortex, especially with the cingulate cortex (53).…”

Section: Possible Role Of Preserved A13 In Pdmentioning

confidence: 98%

“…Current treatments such as pharmacological medications, deep brain stimulation (DBS) and physical therapies lead to only partial gait improvements and these remain major problems in advanced stages of PD (5,6). While subthalamic nucleus (STN) and globus pallidus (GPi) are common DBS targets for PD, alternative targets such as pedunculopontine nucleus (PPN) and the zona incerta (ZI) have been proposed with mixed results in improving postural and/or gait dysfunctions (6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Part of the issue with targeting the ZI with DBS strategies is the relative lack of knowledge regarding its downstream anatomical and functional connectivity with motor centres.…”

Section: Introductionmentioning

confidence: 99%

Substantia nigra degradation results in widespread changes in medial zona incerta afferent and efferent connectomics

Kim

Chomiak

Tran

et al. 2021

Preprint

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Parkinson disease (PD) is a complex disease affecting many facets of movement, especially gait abnormalities such as shuffling and freezing of gait. The nigrostriatal pathways of the basal ganglia are traditionally targeted by existing therapies; however, other pathways may be more relevant to gait, such as the pedunculopontine nucleus and the zona incerta (ZI). The A13 nucleus may be such a target as it has emerged as an area of interest in dopamine motor function. Yet, this area remains understudied compared to other dopamine nuclei, especially in animal models of PD. In 6-OHDA mice, we found a reduction in locomotion in the open field and gait dysfunction during treadmill tests. Medial ZI dopamine cells, containing the A13 nucleus, were preserved following 6-OHDA, in contrast to a marked reduction in substantia nigra pars compacta (SNc) neurons. There was extensive remodelling of the A13 afferent and efferent connectome following nigrostriatal lesions. Afferent input patterns displayed a marked reduction in cross-correlation across brain regions in 6-OHDA mice, while efferent projections showed an increase. In a human PD patient with advanced gait dysfunction we found that the A13 nucleus was preserved, suggesting that remodelling could also occur in humans. This work points to the A13 region as a potential therapeutic target in PD.

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“…However, when feasible, the protocol for individualized TDI reconstruction proposed in the present work could be employed to get a more precise and patient-tailored target identification. In addition, such approach could provide further information also on some extra-thalamic structures of known surgical interest, such as the ansa lenticularis, the zona incerta or the mammillothalamic tract (Rossi et al 2016;Balak et al 2018;Ossowska 2020).…”

Section: Implications For Stereotactic Targeting In Functional Neurosmentioning

confidence: 99%

In vivosuper-resolution track-density imaging for thalamic nuclei identification

Basile

Bertino

Bramanti

et al. 2021

Preprint

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The development of novel techniques for the in vivo, non-invasive visualization and identification of thalamic nuclei has represented a major challenge for human neuroimaging research in the last decades. Thalamic nuclei have important implications in various key aspects of brain physiology and many of them show selective alterations in various neurologic and psychiatric disorders. In addition, both surgical stimulation and ablation of specific thalamic nuclei have been proven to be useful for the treatment of different neuropsychiatric diseases. The present work aimed at describing a novel protocol for histologically-guided delineation of thalamic nuclei based on short-tracks track-density imaging (stTDI), which is an advanced imaging technique that exploits high angular resolution diffusion tractography to obtain super-resolved white matter maps with high anatomical information. We tested this protocol on i) six healthy individual 3T MRI scans from the Human Connectome Project database, and on ii) a group population template reconstructed by averaging 100 unrelated healthy subjects scans from the same repository. We demonstrated that this approach can identify up to 13 distinct thalamic nuclei bilaterally with very high reliability (intraclass correlation coefficient: 0.996, 95% CI: 0.993-0.998; total accumulated overlap: 0.43) and that both subject-based and group-level thalamic parcellation show a fair share of similarity to a recent standard-space histological thalamic atlas. Finally, we showed that stTDI-derived thalamic maps can be successfully employed to study thalamic structural and functional connectivity, and may have potential implications both for basic and translational research, as well as for pre-surgical planning purposes.

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Zona incerta as a therapeutic target in Parkinson’s disease

Cited by 51 publications

References 146 publications

Homologous organization of cerebellar pathways to sensory, motor, and associative forebrain

Homologous organization of cerebellar pathways to sensory, motor, and associative forebrain

Substantia nigra degradation results in widespread changes in medial zona incerta afferent and efferent connectomics

In vivosuper-resolution track-density imaging for thalamic nuclei identification

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