Journal of Neural Transmission (2024) 131:1329–1339

https://doi.org/10.1007/s00702-024-02813-y

NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - REVIEW ARTICLE

Neuroplasticity in Parkinson’s disease

Bogdan Ovidiu Popescu1,2 · Lucia Batzu3,4 · Pedro J. Garcia Ruiz5 · Delia Tulbă1 · Elena Moro6 · Patrick Santens7,8

Received: 6 July 2024 / Accepted: 22 July 2024 / Published online: 5 August 2024
© The Author(s) 2024

Abstract
Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder, affecting millions of people and rapidly
increasing over the last decades. Even though there is no intervention yet to stop the neurodegenerative pathology, many
efficient treatment methods are available, including for patients with advanced PD. Neuroplasticity is a fundamental prop-
erty of the human brain to adapt both to external changes and internal insults and pathological processes. In this paper we
examine the current knowledge and concepts concerning changes at network level, cellular level and molecular level as
parts of the neuroplastic response to protein aggregation pathology, synapse loss and neuronal loss in PD. We analyse the
beneficial, compensatory effects, such as augmentation of nigral neurons efficacy, as well as negative, maladaptive effects,
such as levodopa-induced dyskinesia. Effects of physical activity and different treatments on neuroplasticity are considered
and the opportunity of biomarkers identification and use is discussed.

Keywords Parkinson’s disease · Neuroplasticity · Biomarkers · Dopamine · NMDA · AMPA · BDNF

Abbreviations ASL Arterial spin labelling

α -Syn α-Synuclein BDNF Brain-derived neurotrophic factor
AMPA α-Amino-3-hydroxyl-5-methyl-4-isoxazole- cAMP Cyclic adenosine monophosphate
propionate CaMKII Calcium/calmodulin-dependent protein
kinase II
CSF Cerebrospinal fluid
* Bogdan Ovidiu Popescu DBS Deep brain stimulation
bogdan.popescu@umfcd.ro
dMSN Medium spiny striatal neurons of the direct
1
Department of Clinical Neurosciences, ‘Carol Davila’ pathway
University of Medicine and Pharmacy Bucharest, Bucharest, DNA Deoxyribonucleic acid
Romania GPe Globus pallidus external part
2
Laboratory of Cell Biology, Neurosciences and Experimental IGF-1 Insulin-like growth factor-1
Myology, ‘Victor Babeș’ National Institute of Pathology, iMSN Medium spiny striatal neurons of the indirect
Bucharest, Romania
pathway
3
Department of Basic and Clinical Neuroscience, Institute Kir Inward-rectifying potassium current
of Psychiatry, Psychology and Neuroscience, The Maurice
Wohl Clinical Neuroscience Institute, King’s College LID Levodopa-induced dyskinesia
London, London, UK LTD Long term depression
4
Parkinson’s Foundation Centre of Excellence, King’s College LTP Long term potentiation
Hospital, London, UK MAPK Mitogen-activated protein kinase
5
Department of Neurology, Fundacion Jimenez Diaz, Madrid,
MRI Magnetic resonance imaging
Spain NMDA N-methyl-D-aspartate
6
Division of Neurology, Centre Hospitalier Universitaire de
PD Parkinson’s disease
Grenoble, Grenoble Alpes University, Grenoble Institute PET Positron emission tomography
of Neuroscience, INSERM U1216, Grenoble, France PFFs Preformed fibrils
7
Department of Neurology, University Hospital Ghent, Ghent, PINK1 PTEN-induced kinase 1
Belgium PKA Protein kinase A
8
Faculty of Medicine and Health Sciences, Ghent University, PKC Protein kinase C
Ghent, Belgium

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1330 B. O. Popescu et al.

STN Subthalamic nucleus and learning, genetic factors, healthy state/comorbidities of

sVCAM-1 Serum soluble vascular adhesion molecule 1 the individual, exercise, diet and sleep, age being the most
TOM Translocase of the outer membrane important (Pickersgill et al. 2022). A reduction in neuroplas-
TIM23 Mitochondrial import inner membrane trans- ticity with age, however, might not only be an effect of cells
locase subunit TIM23 own biological clock. It might be so because we need a set
TMS Transcranial magnetic stimulation of unchangeable neural networks defining our own selves,
TNF-alpha Tumor necrosis factor-alpha our personal identities as individuals.

Physiological versus pathological neuroplasticity

Introduction
Physiological neuroplasticity refers to the ability of the brain
The quality of our brain activity, measured by functional to modify, change and adapt as a result of normal sensory,
performance, depends both on the number of neurons motor, and cognitive experiences. This type of neuroplas-
(mass effect) and the connections between them (relation- ticity is commonly positive, functional, and beneficial,
ship effect), enabling complex neurocircuitry. Complexity promoting learning and healthy brain development (Mor-
of behaviour is always possible due to the complexity of the ris et al. 1990). Engaging in new learning activities stimu-
underlying brain networks. Brain aging and neurodegenera- lates synaptic plasticity, through complex molecular events,
tion, associated with an overall decrease of brain connectiv- mainly linked to long term potentiation (LTP). LTP is a pro-
ity to different extents and timing for each individual, might cess where synaptic connections between neurons become
be seen as a reversal of brain development, when brain con- stronger with frequent activation and involves glutamatergic
nectivity is increased. Aging neurons can be seen as aging signalling through ionotropic α-amino-3-hydroxyl-5-methyl-
humans, more fragile, and vulnerable, but still able to func- 4-isoxazole-propionate (AMPA) (Diering and Huganir 2018)
tion and communicate. This review paper aims to look at and N-methyl-D-aspartate (NMDA) (Park et al. 2013)
neuroplasticity in an important neurodegenerative disorder, receptors. The resulting calcium influx activates calcium/
Parkinson’s disease (PD), shedding light on the mechanisms calmodulin-dependent protein kinase II (CaMKII) – Nicoll
of communication adaptation under conditions of aging and and Schulman 2023, protein kinase C (PKC), and mitogen-
death in the neuronal world of human brain. activated protein kinase (MAPK). With high-rate stimulation
of neuronal networks, changes in AMPA receptor traffick-
Neuroplasticity – definition and concept ing occur, with externalisation of more AMPA receptors on
the neuronal membranes, increasing the postsynaptic sen-
Neuroplasticity is a fundamental property of the human sitivity to glutamate and enhancing the synaptic strength
brain that enables it to learn from and adapt to various expe- (Lisman 2017). Meanwhile, changes in gene expression and
riences. This property was described for the first time by protein synthesis take place, making the structural changes
Ramon Y Cajal, in 1984, in the Croonian lecture: ‘the cere- possible at the synapse level, with growth of new synaptic
bral cortex is similar to a garden filled with trees, the pyram- connections and strengthening of the existing ones. Over
idal cells, which, thanks to intelligent culture, can multiply time, sustained LTP leads to permanent changes in neuronal
their branches, sending their roots deeper and producing terminal structures, including increased dendritic branching
more and more varied and exquisite flowers and fruits.’ and new synaptic contacts, further stabilizing the enhanced
(Jones 1994). The brain is in permanent change throughout signalling between neurons in the specific activated network
life, continuing to reorganize pathways and create new con- (Kuba and Kumamoto 1990). Opposed to LTP, when a neu-
nections (Byrne et al. 1990). Neuroplasticity does occur at ronal network is not stimulated for a significant period of
various levels ranging from molecular alterations (e.g. pro- time, long term depression (LTD) occurs (Connor and Wang
tein expression, receptors externalisation) to cellular changes 2016) which results in loss of the function of the respective
due to learning, to large scale cortical remapping in response neuronal network (‘forgetting’).
to injury. The ability of the brain to rewire itself holds sig- Physiological neuroplasticity is subject to a complex reg-
nificant implications for developmental sciences, neurologi- ulation. Trophic factors, such as brain-derived neurotrophic
cal recovery and medical rehabilitation (Seng et al. 2022). factor (BDNF – Fakhoury et al. 2022), neurotransmitters
In the field of neurodegeneration, it is particularly important (such as serotonin – Higa et al. 2024 or dopamine – Bech
how the surviving neurons adapt to the loss of other neu- et al. 2023), dedicated genes (such as Nogo-A – Schwab
rons and how they succeed to compensate for the neural 2010) or even cells (such as microglia – You et al. 2024
networks through new connections or increased delivery of and astrocytes—Andrade-Talavera et al. 2023) are able
neurotransmitters (Enciu et al. 2011). There are well known to stimulate or limit the capacity of neurons to make new
factors influencing neuroplasticity, such as age, experience connections.
Neuroplasticity in Parkinson’s disease 1331

We use here the term pathological neuroplasticity for mesencephalic and nigral neurons. Dopamine exerts oppo-
changing in connections and rewiring in pathological con- site effects on both pathways with excitatory effects on D1
ditions, such as traumatic brain injury, stroke, neurodegen- receptors in the medium spiny striatal neurons of the direct
erative disorders or any other insults or conditions. While pathway (dMSN), and inhibitory action on D2 receptors of
this type of plasticity can lead to functional adaptations that neurons of the indirect pathway (iMSN) (DeLong and Wich-
help the brain to compensate for damage, it can also result in mann 2009). Dopamine release occurs both a phasically and
maladaptive changes that exacerbate dysfunction or manifest tonically. Phasic release is dependent on reward and creates a
as neurological or psychiatric symptoms. A typical example critical time window of a few seconds that allows to induce
of such a maladaptive neuroplastic response is late-onset plasticity in corticostriatal dMSN and iMSN synapses
vascular epilepsy, where after a stroke the new network related to the preceding action (Andrzejewski et al. 2013).
formation leads to formation of a seizure focus (Heuts-van Although this model allows the prediction of some clini-
Raak et al. 1996). For the subject of this review, the most cal observations, there are still many gaps, which are only
discussed issue of maladaptive (or aberrant) neuroplasticity partially filled by subsequent modifications of the model,
is levodopa-induced dyskinesia (Bove et al. 2024). At the such as the addition of the hyperdirect pathway, bypassing
other end of this view, the useful compensatory neuroplas- the striatum and directly delivering cortical information to
ticity is represented here by the capacity of neurons in sub- the subthalamic nucleus (STN), and the connectivity of sub-
stantia nigra pars compacta to adapt and increase the supply cortical nuclei with brainstem reticular and cerebellar nuclei
of dopamine in the striatum for a long period of time. It is (Doyon and Benali 2005).
known that the onset of motor signs of parkinsonism occurs
only when the number of nigral neurons decrease to around Corticostriatal pathways
30–50% (Lang and Losano 1998, Dauer and Przedborski
2003). There is data suggesting that the surviving nigral neu- Most of our knowledge on synaptic plasticity in the basal
rons do undergo important plastic changes at the level of ganglia and its alterations in pathological conditions such
protein expression, enzymatic transformation of levodopa to as Parkinson’s Disease (PD) refers to corticostriatal con-
dopamine, axonal terminals contacts in the striatum, which nections and striatal interneurons, largely ignoring plastic
succeed to compensate the cellular loss for a period of time alternations in other basal ganglia nuclei. The striatum
(Cheng et al. 2010). However, if we consider the progressive receives massive glutamatergic projections to medium spiny
neurodegeneration illustrated by Braak’s pathological stages neurons from numerous cortical regions (Gómez-Ocádiz and
of PD (Braak et al. 2002), such compensatory neuroplastic Silberberg 2023). The main mechanisms of plasticity are
events might be predicted for stage IV (transitional stage different in the direct and indirect pathway (Jin and Costa
affecting basal ganglia) and V-VI (cortical stages). 2015). In the direct pathway a classical LTP mechanism is
predominant; it requires the activation of NMDA-receptors
Basal ganglia pathways and synaptic plasticity and intracellular kinases, which is promoted by D1 receptor
activation in dMSN by dopamine release. In the indirect
The basal ganglia are involved in a multiplicity of motor and pathway plasticity is dominated by LTD, which relies heav-
behavioural functions. Most importantly they are implicated ily on retrograde endocannabinoid signalling (Lovinger,
in implicit memory formation, motor learning and automa- 2010). Activation of metabotropic receptors and the ensuing
tion of movement and behaviour (Holly et al. 2024). These Ca-influx in iMSN generates the retrograde release of endo-
functions are heavily dependent on the potential of synaptic cannabinoids which lower glutamate release from presynap-
plasticity within the basal ganglia circuitry, and hence on the tic corticostriatal afferents by activation of endocannabinoid
functional organization of cortico-subcortical networks (Del receptors. LTD is further promoted by dopaminergic acti-
Rey and García-Cabezas 2023). vation of D2receptors. Interneurons in the striatum releas-
The classical description of this organization is based on ing acetylcholine to muscarinic receptors of medium spiny
the original model of Alexander and DeLong (DeLong et al. neurons attenuate synaptic plasticity through the lowering
1984), which has undergone several modifications follow- of Ca-influx and kinase activation as well as promoting LTD
ing clinical observations, neuroimaging data, electrophysi- (Lovinger 2010). The effects of nitric oxide and adenosine
ological and neurochemical research in humans as well as in further shape the potential of synaptic plasticity in the stria-
animals. However, one of the basic principles of the original tum (Shen et al. 2022, Scarduzio et al. 2022).
models has prevailed, which is the existence of a pathway Progressive degeneration of dopaminergic terminals in
promoting movement and action (the “direct” pathway) and the striatum is a hallmark of PD. The onset of motor symp-
a separate inhibitory pathway (the “indirect” pathway). The toms occurs after a loss of some 50–60% of nigrostriatal
balance between both pathways is maintained by the release afferents, which corresponds to a loss of 30% of dopamin-
of dopamine in the striatum from the terminals of ventral ergic neurons in substantia nigra (Cheng et al. 2010). A
1332 B. O. Popescu et al.

decrease of dopaminergic innervation at dMSN and iMSN dampens glutamatergic actions at hyperexcitable dMSN
leads to a profound reorganization of synaptic plasticity. In (Duty 2012).
the early stages phasic dopamine release will progressively This review of neuroplasticity in corticostriatal connec-
decrease, disturbing context-dependent synaptic plasticity tions is far from a final picture. Recent research has indicated
(Madadi Asl et al. 2022). Mechanisms underlying gluta- that the segregation of direct and indirect pathways may not
mate-induced LTP are no longer supported, affecting mainly be as rigid as formerly thought; the existence of collaterals
dMSN-related plasticity. Due to the loss of D2receptor acti- between both pathways has been shown, as well as the exist-
vation, LTD is affected through a decrease of retrograde ence of D1/D2 heterodimers (Gagnon et al. 2017). These
endocannabinoid signalling, with a major effect on iMSN recent findings demonstrating the intertwining of direct and
and indirect pathway related plasticity. Dopaminergic loss indirect pathways further complicate our understanding of
thus contributes not only to hypokinesia as predicted by the synaptic plasticity in the basal ganglia circuitry.
model, but also to an impairment of implicit learning and
automation of movement and behavior, underlying the major The STN and the hyperdirect pathway
difficulty encountered in the rehabilitation of PD patients
(Madadi Asl et al. 2022). As dopaminergic degeneration pro- More recent versions of the basal ganglia circuitry have
gresses to a near total loss of striatal dopaminergic terminals attributed a more central role for the activity of the STN. The
there is a progressive loss of the potential for synaptic plas- STN is a relay nucleus in the indirect pathway of the basal
ticity, which correlates with the increasing need to rely on ganglia circuitry, with GABA-ergic connections from the
external cues and non-automatic behaviour in PD patients, external pallidum (DeLong et al. 1984). In addition, the STN
placing additional stress on working memory and cognitive is a direct input nucleus, receiving somatotopically organ-
resources (Cousineau et al. 2022). ized glutamatergic inputs from the cortex. The latter is called
An important phenomenon that follows a loss of dopa- the hyperdirect pathway (Nambu et al. 2002). The output
minergic input to MSN in the striatum is the increase of of the STN is an excitatory glutamatergic projection to the
excitability, especially in dMSN, related to a reduction of internal pallidum and substantia nigra pars reticulata. The
the inward-rectifying potassium current (Kir), at least in ani- role of the STN in shaping voluntary motor and behavioural
mal models (Li et al. 2024). This increases the excitability responses is undisputed and is illustrated by the observations
of dMSN to incoming stimuli and compromises the forma- resulting from lesions and dysfunctions, such as hemibal-
tion of a balanced motor output (Li et al. 2024). There are lismus. The STN is thought to be critical in the selection of
other mechanisms in progressing PD not directly related to wanted motor programs and suppressing competing ones
dopamine loss that further contribute to the deterioration of (Nambu 2002). This shaping necessitates an early STN exci-
corticostriatal plasticity, including the increase of acetylcho- tation by the hyperdirect pathway and a late excitation from
line release from activated interneurons and the loss of nitric the indirect pathway (Polyakova et al. 2020). It is generally
oxide related “brakes” on glutamatergic activity in iMSN assumed that in PD there is a disinhibition of the excitatory
(Shen et al. 2022, Scarduzio et al. 2022). STN output, resulting in overactive inhibition of thalamic
As levodopa may restore phasic signalling in dMSN in neurons by the internal pallidum, leading to hypokinesia.
the early stages of PD, motor learning may improve under This is also assumed to be the rationale for the success of
treatment. At more advanced stages however, where dopa- STN stimulation in PD patients.
minergic innervation is extremely affected, context-depend- Recent data suggest that the hyperdirect pathway also
ent phasic signalling will be lost in both direct and indirect undergoes neuroplastic changes. In a parkinsonian mouse
pathways, even under treatment, leading to inappropriate model it was shown that the progressive decrease of dopa-
onset of motor activity and impaired motor learning (Albin mine in the striatum triggers a subsequent maladaptive exci-
and Leventhal 2017). It is postulated that levodopa may act tation/inhibition shift in the STN. This phenomenon seems
as a neurotransmitter itself, or that levodopa conversion to to be dependent on NMDA receptor signalling in the STN
dopamine will occur in serotonergic neurons which are not neurons (Chu et al. 2017). With low dopamine levels, there
regulated by the necessary reward-related stimuli (Gantz is an increase in NMDA receptors level which triggers an
et al. 2015). The subsequent loss of temporo-spatially coor- abnormal strengthening of GPe-STN inputs as well (Chu
dinated activation of D1 and D2 receptors prevents a struc- et al. 2015).
tured response to incoming stimuli, leading to random motor In addition, there is evidence for adaptive mechanisms
activation as reflected in dyskinesia. These considerations at the level of the synapses between STN and internal palli-
explain why the occurrence of levodopa-related dyskine- dum, which are able to modify the impact of the hyperdirect
sia requires a degeneration of the dopaminergic system. It pathway on the basal ganglia output nuclei. These neuro-
also offers an explanation for the anti-dyskinetic effects of plastic alterations are suggested to depend on LTD induc-
NMDA-receptor antagonists, such as amantadine which tion by retrograde endocannabinoid signalling (Gorodetski
Neuroplasticity in Parkinson’s disease 1333

et al. 2018), which opens perspectives for pharmacological then several molecular mechanisms must be involved. Pos-
modulation of these synapses in PD. sibly, the most interesting and testable molecular mechanism
includes the release of BDNF (Marino et al 2023; Kowiański
Exercise‑driven plasticity of neural networks in PD et al. 2018; Ruiz-González et al. 2021; Rotondo et al. 2023;
de Sousa 2020); suffice is to recall that BDNF is a crucial
At present, symptomatic antiparkinsonian medication allows neurotrophic factor with multiple roles on regulation of neu-
a relevant motor and functional improvement in PD for rophysiological processes (Ruiz-González et al. 2021). The
many years (Foltynir et al. 2024). In addition to sympto- BDNF isoforms interact with different types of receptors
matic drugs, other non-pharmacological approaches have (including sortolin and p75 neurotrophin receptor) triggering
been advised including physical exercise. As Eric Ahlskog a wide range of signalling cascades (Ruiz-González et al.
already suggested a decade ago, ‘often overlooked (…) is 2021). BDNF has multiple and overlapping mechanism such
the potential benefit of sustained vigorous exercise on PD as anti-apoptotic activity, regulation of protein synthesis,
progression’ (Ahlskog 2011). Physical exercise symptomati- cytoskeleton development, enhancement of dendritic growth
cally improves PD (Comella et al. 1994; Kim et al. 2023) and branching (Marino et al 2023; Kowiański et al. 2018;
and there are clinical and experimental clues to suggest that Ruiz-González et al. 2021; Rotondo et al. 2023; de Sousa
intensive exercise may change the natural evolution of PD 2020). Physical exercise increases plasma BDNF levels in
(Ahlskog 2011, 2018; Garcia Ruiz et al. 2022; Tsukita et al. experimental models and individuals with neurodegenera-
2022). Finally, physical exercise may reduce the risk of PD tive disorders (Marino et al. 2023; Kowiański et al. 2018;
and other neurodegenerative diseases (Xu et al. 2010; Bel- Rotondo et al. 2023) and interestingly, BDNF receptor
visi et al. 2020; Sujkowski et al. 2022). In summary, for blockade prevents the beneficial effects of exercise in animal
many, physical exercise might be the first neuroprotective models (Real et al. 2013).
treatment available for PD (Ahlskog 2011, 2018; Garcia Other potential mechanisms may include elevated expres-
Ruiz et al. 2022; Tsukita et al. 2022). The multiple and sion of anti-inflammatory cytokines, reduced levels of pro-
fascinating mechanisms of exercise include modulation of inflammatory cytokines and activated microglia (Svensson
neuroplasticity. et al. 2015). Mitochondrial function has been also inves-
Physical exercise has been recommended since classic tigated. Overexpression of α-Syn results in mitochondrial
times (Hippocrates and Galen) as a general measure for DNA damage and repressed activation of respiratory chain
health (Tipton 2014), but its mechanism has been completely complex I and IV (Sung et al. 2012). Intensive exercise
unknown for centuries. At present, some of the potential improves mitochondrial machinery in animal models of PD
mechanisms have been studied both in experimental animal (Koo et al. 2017), improves mitophagy through the PINK1/
models and in patients with neurodegenerative diseases. Sev- Parkin signalling pathway and induces the expression of
eral clues suggest that physical exercise may act on many multiple mitochondrial protein import components such
aspects of neuroplasticity (Hirsch et al. 2016; Sacheli et al. as TOM20, TOM22, and TIM23 (Koo et al. 2017; Li et al.
2019; Johansson et al. 2020; Binda et al. 2021; Yu et al. 2023).
2023). Neuroplasticity may explain (at least partially) sev- In summary, exercise is one the main approaches for the
eral clinical and experimental observations such as the long- comprehensive treatment of PD and may influence several
term exercise-related motor benefit, the reduction of brain basic aspects of its pathophysiology (Ahlskog 2011, 2018;
atrophy, the increased functional connectivity of the anterior Binda et al. 2021; Marino et al. 2023). Exercise acts on sev-
putamen, the enhanced dopamine release, and the increased eral aspects of neuroplasticity and probably can positively
striatal synaptic integrity in animal models (Hirsch et al. change the natural evolution of PD (2,10–15 Ahlskog 2011,
2016; Sacheli et al. 2019; Johansson et al. 2020; Binda et al. 2018; Yoon et al. 2021; Garcia Ruiz et al. 2022; Tsukita
2021; Yu et al. 2023; Marino et al 2023). The exact mecha- et al. 2022).
nisms of exercise-related neuroplasticity are unknown, but
several relevant findings have been found. Levodopa‑induced dyskinesia and aberrant
Recently, Marino et al (2023) studied the synaptic mech- neuroplasticity
anisms underlying exercise-induced plastic effects on the
striatal synaptic connections. In a very elegant experimental Neuroplasticity is central to understanding the pathophysi-
PD animal model, using bilateral intrastriatal injection of ology of levodopa-induced dyskinesia (LID), a common
α-synuclein (α -Syn) preformed fibrils (PFFs) they observed and debilitating complication in PD therapy in moderate to
loss of LTP in striatal spiny projection neurons. After inten- advanced PD patients. The adaptive capacity of the brain
sive exercise, a lasting rescue of a physiological corticostri- while generally beneficial for recovery from different insults,
atal LTP was observed. If exercise-related neuroplasticity can unfortunately lead as well to maladaptive changes result-
can change the synaptic striatal organization and function, ing in clinical complications, such as those observed in
1334 B. O. Popescu et al.

LID. Since this subject was extensively reviewed recently refractory depression might be a crucial effect of STN-DBS
(Bove et al. 2024) we will mention here only the main cur- which might explain the alleviation of LID (Milosevic et al.
rent information regarding LID. The molecular mechanisms 2018).
underlying LID-associated neuroplasticity involve com- Reviewing the general mechanisms of electrical brain
plex alterations in dopamine receptor signalling pathways. stimulation, McIntyre and Anderson postulate that these are
Prolonged levodopa oral (intermittent) treatment leads to multiple and at different levels: ionic level, protein level,
heightened sensitivity and responsiveness of D1 receptors cellular level and network level, claiming that DBS might
on the dMSNs in the striatum (Guigoni et al. 2005). This be considered a chemical therapy, since it results in action
sensitisation results in the dysregulation of cAMP/PKA sig- potential, orthodromic and antidromic propagation of action
nalling pathway and an increase in glutamate neurotransmis- potentials and finally a very high number of synaptic events
sion, facilitating excessive and uncontrolled motor outputs (McIntyre and Anderson 2016). Repeated high frequency
(Serra et al. 2021). Additionally, the neuroplastic changes stimulation is to be expected to result in neuroplasticity
in LID are associated with altered expression and function activation, as physiologically happen in LTP, for instance,
of other neurotransmitter systems, further complicating the as well. A report suggests that STN stimulation activates
synaptic environment and motor outcomes. For instance, antidromically the hyperdirect pathway, the action poten-
alterations in the serotoninergic system, which compensates tials reaching the cortex and inducing a profound synaptic
for dopamine loss, can exacerbate dyskinesia due to its role suppression, with effects on synaptic networks functioning
in modulating striatal output pathways (Cirillo et al. 2024). (Anderson et al. 2018).
Probably there are ways to interfere with this aberrant neuro- Since the neurobiological outcomes can be much easier
plastic process – a recent review suggests, for instance, that dissected out in animal models, PD murine models exposed
cotreatment with dopamine agonist alters the maladaptive to DBS were explored from different experimental perspec-
changes (Espa et al. 2023). tives. Helf and collaborators used a rat 6-hydroxydopamine
PD model with STN stimulation and showed that after
Deep brain stimulation effects on neuroplasticity one week, the intervention group had 3.5 more tyrosine-
in PD hydroxylase positive neurons in the substantia nigra pars
compacta as compared to the control group, suggesting a
Deep brain stimulation (DBS) implies a brain surgical pro- neurorestorative effect of the high frequency stimulation
cedure/implant which was developed in 1980s based on the (Helf et al. 2023).
theoretical opportunity of electrical modulation of neurocir- Beside possible effects on neuroplasticity, in a rat model
cuitries in the brain (Benabid et al. 1987). DBS proved valu- of PD it was recently shown that DBS is able to significantly
able for different neurological conditions, such as PD, essen- increase neurogenesis as well. Beside improving motor func-
tial tremor, dystonia, epilepsy and it is under evaluation for tion, STN electrical stimulation for 1 week at 130 Hz was
few others. Even though an important number of clinical and able to enhance proliferation of neural stem cells and neu-
electrophysiological studies already explored the effects of roblast in the subventricular zone and to increase dopamin-
this intervention, the exact mechanism of DBS action is still ergic neuronal survival (Wu et al. 2024).
unknown, one of the proposed outcomes being the altera-
tion in local neuronal networks neuroplasticity (Kricheldorff Biomarkers for neuroplasticity in PD – are we there?
et al. 2022). Even the simple insertion of the electrodes,
which is known to transitory confer some symptom relief, Understanding and identifying biomarkers of neuroplasticity
appears to induce a series of brain tissue reactions, includ- in PD is crucial for developing therapeutic strategies aimed
ing inflammation, neurotransmitter release and neuroplastic at enhancing neural adaptability, improving clinical symp-
local circuitry alterations, as seen in histological samples in toms, and ultimately compensating for neurodegeneration.
animal models (Hamani et al. 2024). One of the main issues Potential biomarkers of neuroplasticity in PD should encom-
discussed as DBS effect on neuroplasticity is linked to its pass a range of molecular, cellular, and imaging indicators
efficacy in reducing LID. LID is supposed to develop due that reflect the brain's adaptive changes to specific stimuli
to aberrant neuroplasticity linked to both degeneration and and interventions. These include alterations in neurotrophic
intermittent dopaminergic stimulation and it was claimed factors, synaptic proteins, and functional as well as struc-
that STN DBS might reverse this phenomenon, since dys- tural brain changes. While studies on factors influencing
kinesias diminished in patients who did not decrease levo- neuroplasticity have exponentially increased in the past two
dopa dose after stimulation as well (Figueiras-Méndez et al. decades, biomarkers to assess, quantify and predict neuro-
1999). Using recordings in STN-DBS PD patients, Milose- plasticity have not yet been standardised and validated. This
vic and co-authors suggested that enhancement of inhibi- is partly due to the heterogeneity of changes that can reflect
tory synaptic plasticity with GABA-mediated increasing adaptive brain processes, such as synaptic plasticity. For
Neuroplasticity in Parkinson’s disease 1335

instance, in a recent systematic review and meta-analysis by and/or virtual setting (virtual reality and motor imagery)
Hortobàgyi et al. (2022) assessing the impact of aerobic and in PD have been explored by several studies, which has
resistance training intensity on neuroplasticity in health and been summarised by Baglio et al. in a recent systematic
disease, 74 markers of brain activation, 94 markers of brain review (Baglio et al. 2022). Among the selected studies,
structure, and 76 markers of neurochemicals were extracted the majority used functional MRI (fMRI), either task-
from 50 selected studies (Hortobágyi et al. 2022). based or resting state, with one combining it with arterial
In the context of PD, neuroplasticity biomarkers have spin labelling (ASL) technique (Baglio et al. 2022). Only
been used mainly in studies investigating the effects of one structural MRI study was selected (Sehm et al. 2014).
non-pharmacological interventions. For the purpose of this Overall, the effectiveness of moderate aerobic exercise
review, these can be classified as biofluid-based biomark- seemed to be based on improved functionality within the
ers, imaging biomarkers or biomarkers derived from other cortico-thalamic-striatal pathways, while goal-directed
techniques. exercise seemed to act on supplementary circuitries sup-
porting the sensorimotor integration and reinforcing the
Biofluid‑based biomarkers coupling of premotor areas, often affected in PD since the
early stages (Baglio et al. 2022; Sehm et al. 2014; Silva-
Most clinical studies assessing the effects on neuroplasti- Batista et al. 2020). Interestingly, two studies assessing
city of specific interventions, such as physical activity and the effects of cognitively-enhanced exercise programs,
rehabilitation-based programs, have assessed blood levels showed that the observed clinical improvements in cogni-
of neurotrophins such as brain-derived neurotrophic factor tive and motor symptoms –particularly gait – were associ-
(BDNF) and insulin-like growth factor-1 (IGF-1), among ated with changes in functional connectivity mainly across
others (Rotondo et al. 2023). The greatest evidence in PD the frontoparietal network (Agosta et al. 2017; Maidan
has been gathered so far for BDNF, which is involved in et al. 2017).
neuronal development, synaptic plasticity, LTP, and is In terms of molecular imaging, a small pilot study using
crucial for neurogenesis and synaptic modulation (Park & PET imaging with [18F]fallypride in individuals with
Poo 2013). Serum BDNF levels have been shown to raise early-stage PD showed that intensive exercise led to an
following exercise therapy and seem to be associated with increase in binding potential in the dopamine D2 receptor,
improved motor symptoms, according to the results of two suggesting exercise-derived neuroplasticity in dopaminer-
recent meta-analyses (Kaagman et al. 2024; Paterno et al. gic signalling (Fisher et al. 2013).
2024). However, contrasting results have also been reported
and it is not clear which type of physical activity or rehabili-
tation training could be more effective in increasing blood Other biomarkers
BDNF levels (Rotondo et al. 2023).
Similarly to BDNF, also IGF-1 could be seen as a poten- Few studies have attempted to quantify neuroplasticity
tial biomarker for neuroplasticity in PD, given the possible processes following interventions in PD using alterna-
contribution of impaired insulin/IGF-1 signalling in PD tive methods. For example, Fischer et al. observed a post-
pathophysiology, and the increased IGF-1 levels in serum exercise increase in corticomotor excitability in response
and CSF of PD patients (Godau et al. 2010). However, no to single-pulse transcranial magnetic stimulation (TMS)
significant changes were reported in two studies assessing in a small randomised controlled trial (Fisher et al. 2008).
changes in IGF-1 levels following physical interventions, Interestingly, Mougeot et al. investigated potential
possibly due to the small sample sizes (Rotondo et al. 2023; markers of exercise-induced neuroplasticity in the oral
Soke et al. 2021; Szymura et al. 2020). cavity, based on the hypothesis that exercise can affect the
There is also some evidence for a decrease in inflamma- activity of submandibular glands through noradrenergic
tory cytokines, such as serum tumor necrosis factor-alpha inputs (Mougeot et al. 2016).
(TNF-alpha), and basal serum soluble vascular adhesion Overall, the current evidence for reliable biomarkers
molecule 1 (sVCAM-1) in response to moderate-intensity of neuroplasticity is limited by small sample sizes and
interval training in PD, suggesting that reduced inflamma- heterogeneous definitions of neuroplasticity. The correla-
tion may contribute to increased neuroplasticity observed tion with clinical improvements (motor and/or non-motor)
with physical training (Zoladz et al. 2014). is yet to be clarified for most of the proposed biomarkers.
Additionally, neuroplasticity in PD has been investigated
Imaging biomarkers mostly for exercise-based interventions, therefore limit-
ing the use of these markers in relation to other types of
Functional and structural brain changes in response to interventions, including pharmacological.
physical exercise (aerobic, resistance, endurance, etc.)
1336 B. O. Popescu et al.

Conclusions stimulation. Brain Stimul 11(5):1140–1150. https://​doi.​org/​10.​

1016/j.​brs.​2018.​05.​008
Andrzejewski ME, McKee BL, Baldwin AE, Burns L, Hernandez P
Our brain has an extraordinary capacity to adapt not only (2013) The clinical relevance of neuroplasticity in corticostriatal
to external conditions but also to internal problems, such as networks during operant learning. Neurosci Biobehav Rev 37(9
insults and pathology. Using specific endogenous defence Pt A):2071–2080. https://​doi.​org/​10.​1016/j.​neubi​orev.​2013.​03.​
019
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the pathology for a period of time. Unfortunately, there are roplasticity mediated by motor rehabilitation in Parkinson’s
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sia. Further studies should focus on possible therapeutical revne​uro-​2021-​0064
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targets to increase the compensatory effects and limit the Petersen CCH, Pulin M, Renard A, Sourmpis C (2023) Stri-
maladaptive effects of neuroplasticity in PD. In any case, atal dopamine signals and reward learning. Function Oxf
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Acknowledgements This work was supported by the Ministry of ease development, progression and clinical subtypes of Parkin-
Research, Innovation, and Digitalization in Romania, under the son’s disease: what do prospective studies suggest? Neurobiol
National Program 1N/2019/PN 19.29.02.01 and 1N/2023/ PN Dis 134:104671. https://​doi.​org/​10.​1016/j.​nbd.​2019.​104671
23.16.01.02. Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J (1987)
Combined (thalamotomy and stimulation) stereotactic surgery
Data availability Not applicable. of the VIM thalamic nucleus for bilateral Parkinson disease.
Appl Neurophysiol 50(1–6):344–346. https://​doi.​org/​10.​1159/​
Open Access This article is licensed under a Creative Commons Attri- 00010​0803
bution 4.0 International License, which permits use, sharing, adapta- Binda KH, Lillethorup TP, Real CC, Bærentzen SL, Nielsen MN,
tion, distribution and reproduction in any medium or format, as long Orlowski D, Brooks DJ, Chacur M, Landau AM (2021) Exer-
as you give appropriate credit to the original author(s) and the source, cise protects synaptic density in a rat model of Parkinson’s
provide a link to the Creative Commons licence, and indicate if changes disease. Exp Neurol 342:113741. https://​d oi.​o rg/​1 0.​1 016/j.​
were made. The images or other third party material in this article are expne​urol.​2021.​113741
included in the article’s Creative Commons licence, unless indicated Bove F, Angeloni B, Sanginario P, Rossini PM, Calabresi P, Di Iorio
otherwise in a credit line to the material. If material is not included in R (2024) Neuroplasticity in levodopa-induced dyskinesias: An
the article’s Creative Commons licence and your intended use is not overview on pathophysiology and therapeutic targets. Prog
permitted by statutory regulation or exceeds the permitted use, you will Neurobiol 232:102548. https://​doi.​org/​10.​1016/j.​pneur​obio.​
need to obtain permission directly from the copyright holder. To view a 2023
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