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Associated Neurotransmitters
editDopamine
The main neurotransmitter thought to be involved in hypokinesia is dopamine [1][2]. Essential to the basal ganglionic-thalamo-cortical loop, which processes motor function, dopamine depletion is common in these areas of hypokinesic patients [2]. Bradykinesia is correlated with lateralized dopaminergic depletion in the substantia nigra [2]. The dopamine pathway in the substantia nigra is essential to motor function, and commonly a lesion in this area correlates with displayed hypokinesia [3][2]. Tremor and rigidity, however, seem to be only partially due to dopamine deficits in the substantia nigra, suggesting that there are other processes involved in motor control [2]. Treatments for hypokinesia often either attempt to inhibit the uptake of dopamine or increase the amount of neurotransmitter present in the system [3][2].
GABA and Glutamate
The inhibitory neurotransmitter GABA and the excitatory glutamate are found in many parts of the central nervous system, including in the motor pathways that involve hypokinesia. In one pathway, glutamate in the substantia nigra excites the release of GABA into the thalamus, which then inhibits the release of glutamate in the cortex and thereby reduces motor activity. If there is too much glutamate initially in the substantia nigra, then through interaction with GABA in the thalamus and glutamate in the cortex, movements will be reduced or will not occur at all [4].
Another direct pathway from the basal ganglia sends GABA inhibitory messages to the globus pallidus and substantia nigra, which then send GABA to the thalamus. In the indirect pathway the basal ganglia sends GABA to the globus pallidus which then sends it to the subthalamic nucleus, which then disinhibited sends glutamate to the output structures of the basal ganglia. Inhibition of GABA release could disrupt the feedback loop to the basal ganglia and produce hypokinesic movements. [5]
GABA and glutamate often interact with each other and with dopamine directly. In the basal ganglia, there is a nigrostriatal pathway where GABA and dopamine are housed in the same neurons and released together [6].
Motor Motivation
editOften debated is whether the efficiency, vigor, and speed of movements in patients with hypokinesia are tied to motivation for rewarding and against punishing stimuli. The basal ganglia has been tied to the incentives behind movement, therefore suggesting that a cost/benefit analysis of planned movement could be affected in hypokinesia. Interestingly, rewards have not been shown to change the aspects of a hypokinesic individual’s movement [7]. In fact, the motor planning and control of a patient with hypokinesia is already as efficient as possible (as shown by slightly faster but generally the same movement after DBS of the subthalamic nucleus)[8]. This suggests that hypokinetic individuals simply have a narrower range of movement that does not increase relative to motivation [7][9].
Other studies have come to the same conclusion about rewards and hypokinesia but have shown that aversive stimuli can, in fact, reduce hypokinesic movement. Shiner et al., in their assessment of this finding, suggest that dopamine is either less involved or has a more complex role in the response to punishment than it does to rewards, as the hypodopaminergic striatum allows more movement in response to aversive stimuli [10].
Cognitive Impairment
editBradykinesia has been shown to precede impairment of executive functions, working memory, and attention[1][11]. These cognitive deficiencies can be tied to non-function of the basal ganglia and pre-frontal cortex, which is also linked to the motor-dysfunction of hypokinesia [1]. Tremor and rigidity have not had observable connections to cognitive impairments, supporting the idea that they are not as involved in the dopamine pathway in the basal ganglionic-thalamo-cortical loop [1][2]. Dopaminergic treatments have shown improvement in cognitive functions associated with hypokinesia, suggesting they are also dependent on dopamine levels in the system [11].
Connections to Other Medical Conditions
edit- Stroke- Frontal and subcortical lesions due to stroke more likely to cause hypokinesia than posterior lesions.[12]
- Schizophrenia- Lack of connections between right supplementary motor area to the pallidum and the left primary motor cortex to the thalamus shown in patients with schizophrenia which is thought to lead to hypokinesia. [13]
- Hyperammonia- Chronic hyperammonia and liver disease can alter neurotransmission of GABA and glutamate by increasing the amount of glutamate in the substantia nigra and inhibiting movement. [4]
- Progressive supranuclear palsy- Very similar to Parkinson’s disease, supranuclear palsy does not actually display hypokinetic characteristics of movement (no progressive decrement despite small amplitude). Hypokinesia can help to distinguish this disorder from Parkinson’s. [14]
Treatments
editDopaminergic drugs are commonly used in the early stages of the hypokinesia to treat patients [3]. However, with increased intake they can become ineffective because of the development of noradrenergic lesions [3]. While initially the dopaminergic drugs may be effective, these noradrenergic lesions are associated with hypokinesic gait disorder development later on [3][2].
Once the reaction to dopaminergic drugs begins to fluctuate in Parkinson’s patients, Deep Brain Stimulation (DBS) of the subthalamic nucleus and medial globus pallidus is often used to treat hypokinesia [3][15][16]. DBS, like dopaminergic drugs, initially provides relief but chronic use causes worse hypokinesia and freezing of gait [3][17]. Lower frequency DBS in non-regular patterns has been shown to be more effective and less detrimental in treatment [16][17].
Methylphenidate, commonly used to treat ADHD, has been used in conjunction with levodopa to treat hypokinesia in the short-term [3]. The two work together to increase dopamine levels in the striatum and prefrontal cortex [3]. Methylphenidate mainly inhibits dopamine and noradrenaline reuptake by blocking presynaptic transporters and levodopa increases the amount of dopamine, generally improving hypokinesic gait [3][14]. Some patients, however, have adverse reactions of nausea and headache to the treatment and the long-term effects of the drug treatment still need to be assessed [3].
Another treatment that is still in an experimental stage is the administration of nociception FQ peptide (NOP) receptor antagonists. This treatment has been shown to reduce hypokinesia in animal studies when increasing nociception FQ in the substantia nigra and subthalamic nucleus. Low doses can be taken with dopaminergic treatment to decrease the amount of L-dopa needed, which can reduce its long-term side effects and improve motor performance.[18]
Dance therapy has also been shown to reduce hypokinesic movements and rigidity, though targeted more at the muscular aspects of the disorder than the neural activity.[19]
Demographic Differentiation
editGender
More men than women typically develop hypokinesia, which is reflected in young and middle aged populations where females have displayed higher levels of nigrostriatal dopamine than males. In the elderly, however, this differentiation is not present. Typically, women exhibit more tremor in the beginning development of hypokinesia. In the disorder, men tend to display more rigidity and women more bradykinesic motor behavior, though this is not true in all cases.[20]
Age of Onset
Hypokinesia is displayed in the brain and outwardly slightly different depending on when an individual is first affected. In young-onset hypokinesia (younger than 45 years of age), there is typically slightly more cell loss in the substantia nigra and more displayed dystonia and muscle stiffness. In old-onset hypokinesia (older than 70 years of age), there is typically more of a hypokinesic gait and difficulty walking and no dystonia. Both onsets can display resting tremor, although more generally found in old-onset cases.[21]
References
edit- ^ a b c d Domellöf, Magdalena Eriksson; Elgh, Eva; Forsgren, Lars (2011). "The relation between cognition and motor dysfunction in drug-naive newly diagnosed patients with Parkinson's disease". Movement Disorders. 26 (12): 2183–2189. doi:10.1002/mds.23814. PMID 21661051. S2CID 12462072.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: date and year (link) - ^ a b c d e f g h Vingerhoets, F. J.; Schulzer, M.; Calne, D. B.; Snow, B. J. (1997). "Which clinical sign of Parkinson's disease best reflects the nigrostriatal lesion?". Annals of Neurology. 41 (1): 58–64. doi:10.1002/ana.410410111. PMID 9005866. S2CID 12046814.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: date and year (link) - ^ a b c d e f g h i j k Moreau, Caroline; et al. (2012). "Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial". The Lancet Neurology. 11 (7): 589–596. doi:10.1016/S1474-4422(12)70106-0. PMID 22658702. S2CID 6934138.
{{cite journal}}: Unknown parameter|month=ignored (help)CS1 maint: date and year (link) - ^ a b Llansola, M.; Montoliu, C.; Cauli, O.; Hernández-Rabaza, V.; Agustí, A.; Cabrera-Pastor, A.; Giménez-Garzó, C.; González-Usano, A.; Felipo, V. (2013 Jun). "Chronic hyperammonemia, glutamatergic neurotransmission and neurological alterations". Metabolic Brain Disease. 28 (2): 151–4. doi:10.1007/s11011-012-9337-3. PMID 23010935. S2CID 254795073.
{{cite journal}}: Check date values in:|date=(help) - ^ Ortez, C (2013 Dec 15). "Infantile parkinsonism and gabaergic hypotransmission in a patient with pyruvate carboxylase deficiency". Gene. 532 (2): 302–6. doi:10.1016/j.gene.2013.08.036. PMID 23973720.
{{cite journal}}: Check date values in:|date=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ González-Hernández, T.; Barroso-Chinea, P.; Acevedo, A.; Salido, E.; Rodríguez, M. (2001 Jan). "Colocalization of tyrosine hydroxylase and GAD65 mRNA in mesostriatal neurons". The European Journal of Neuroscience. 13 (1): 57–67. PMID 11135004.
{{cite journal}}: Check date values in:|date=(help) - ^ a b Baraduc, P.; Thobois, S.; Gan, J.; Broussolle, E.; Desmurget, M. (2013 Jan 9). "A common optimization principle for motor execution in healthy subjects and parkinsonian patients". The Journal of Neuroscience : The Official Journal of the Society for Neuroscience. 33 (2): 665–77. doi:10.1523/JNEUROSCI.1482-12.2013. PMC 6704928. PMID 23303945.
{{cite journal}}: Check date values in:|date=(help) - ^ Horak, FB (1984 Aug). "Influence of globus pallidus on arm movements in monkeys. I. Effects of kainic acid-induced lesions". Journal of Neurophysiology. 52 (2): 290–304. doi:10.1152/jn.1984.52.2.290. PMID 6481434.
{{cite journal}}: Check date values in:|date=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Desmurget, M.; Turner, R. S. (2008 Mar). "Testing basal ganglia motor functions through reversible inactivations in the posterior internal globus pallidus". Journal of Neurophysiology. 99 (3): 1057–76. doi:10.1152/jn.01010.2007. PMC 2906399. PMID 18077663.
{{cite journal}}: Check date values in:|date=(help) - ^ Shiner, T.; Seymour, B.; Symmonds, M.; Dayan, P.; Bhatia, K. P.; Dolan, R. J. (2012). "The effect of motivation on movement: a study of bradykinesia in Parkinson's disease". PLOS ONE. 7 (10): e47138. doi:10.1371/journal.pone.0047138. PMC 3471921. PMID 23077557.
- ^ a b Cuesta, M. J.; Sánchez-Torres, A. M.; De Jalón, E. G.; Campos, M. S.; Ibáñez, B.; Moreno-Izco, L.; Peralta, V. (26). "Spontaneous Parkinsonism Is Associated With Cognitive Impairment in Antipsychotic-Naive Patients With First-Episode Psychosis: A 6-Month Follow-up Study". Schizophrenia Bulletin. 40 (5): 1164–1173. doi:10.1093/schbul/sbt125. PMC 4133659. PMID 24072809.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help) - ^ Kim, E. J.; Lee, B.; Jo, M. K.; Jung, K.; You, H.; Lee, B. H.; Cho, H. J.; Sung, S. M.; Jung, D. S.; Heilman, K. M.; Na, D. L. (2013 Jul). "Directional and spatial motor intentional disorders in patients with right versus left hemisphere strokes". Neuropsychology. 27 (4): 428–37. doi:10.1037/a0032824. PMID 23876116.
{{cite journal}}: Check date values in:|date=(help) - ^ Bracht, T.; Schnell, S.; Federspiel, A.; Razavi, N.; Horn, H.; Strik, W.; Wiest, R.; Dierks, T.; Müller, T. J.; Walther, S. (2013 Feb). "Altered cortico-basal ganglia motor pathways reflect reduced volitional motor activity in schizophrenia". Schizophrenia Research. 143 (2–3): 269–76. doi:10.1016/j.schres.2012.12.004. PMID 23276479. S2CID 20131894.
{{cite journal}}: Check date values in:|date=(help) - ^ a b Ling, Helen; Massey, Luke A.; Lees, Andrew J.; Brown, Peter; Day, Brian L. (6). "Hypokinesia without decrement distinguishes progressive supranuclear palsy from Parkinson's disease". Brain. 135 (4): 1141–1153. doi:10.1093/brain/aws038. PMC 3326257. PMID 22396397.
{{cite journal}}: Check date values in:|date=and|year=/|date=mismatch (help); Unknown parameter|month=ignored (help) - ^ Blomstedt, P.; Fytagoridis, A.; Åström, M.; Linder, J.; Forsgren, L.; Hariz, M. I. (2012 Dec). "Unilateral caudal zona incerta deep brain stimulation for Parkinsonian tremor". Parkinsonism & Related Disorders. 18 (10): 1062–6. doi:10.1016/j.parkreldis.2012.05.024. PMID 22709794.
{{cite journal}}: Check date values in:|date=(help) - ^ a b Brocker, D. T.; Swan, B. D.; Turner, D. A.; Gross, R. E.; Tatter, S. B.; Koop, M. M.; Bronte-Stewart, H.; Grill, W. M. (2013 Jan). "Improved efficacy of temporally non-regular deep brain stimulation in Parkinson's disease". Experimental Neurology. 239: 60–7. doi:10.1016/j.expneurol.2012.09.008. PMC 3547657. PMID 23022917.
{{cite journal}}: Check date values in:|date=(help) - ^ a b Xie, T.; Kang, U. J.; Warnke, P. (2012 Oct). "Effect of stimulation frequency on immediate freezing of gait in newly activated STN DBS in Parkinson's disease". Journal of Neurology, Neurosurgery, and Psychiatry. 83 (10): 1015–7. doi:10.1136/jnnp-2011-302091. PMID 22696586. S2CID 22433681.
{{cite journal}}: Check date values in:|date=(help) - ^ Marti, M (2013 Feb). "Acute and chronic antiparkinsonian effects of the novel nociceptin/orphanin FQ receptor antagonist NiK-21273 in comparison with SB-612111". British Journal of Pharmacology. 168 (4): 863–79. doi:10.1111/j.1476-5381.2012.02219.x. PMC 3631376. PMID 22994368.
{{cite journal}}: Check date values in:|date=(help); Unknown parameter|coauthors=ignored (|author=suggested) (help) - ^ Heiberger, Lisa (2011). "Impact of a weekly dance class on the functional mobility and on the quality of life of individuals with parkinson's disease". Frontiers in Aging Neuroscience. 3: 14. doi:10.3389/fnagi.2011.00014. PMC 3189543. PMID 22013420.
- ^ Solla, P.; Cannas, A.; Ibba, F. C.; Loi, F.; Corona, M.; Orofino, G.; Marrosu, M. G.; Marrosu, F. (2012 Dec 15). "Gender differences in motor and non-motor symptoms among Sardinian patients with Parkinson's disease". Journal of the Neurological Sciences. 323 (1–2): 33–9. doi:10.1016/j.jns.2012.07.026. PMID 22935408. S2CID 30892699.
{{cite journal}}: Check date values in:|date=(help) - ^ Gibb, W. R.; Lees, A. J. (1988 Sep). "A comparison of clinical and pathological features of young- and old-onset Parkinson's disease". Neurology. 38 (9): 1402–6. doi:10.1212/wnl.38.9.1402. PMID 3412587. S2CID 32226788.
{{cite journal}}: Check date values in:|date=(help)