Neurophysiological studies on atypical parkinsonian syndromes

Accepted Manuscript Neurophysiological studies on atypical parkinsonian syndromes Matteo Bologna, Antonio Suppa, Flavio Di Stasio, Antonella Conte, Giovanni Fabbrini, Alfredo Berardelli PII:

S1353-8020(17)30224-9

DOI:

10.1016/j.parkreldis.2017.06.017

Reference:

PRD 3336

To appear in:

Parkinsonism and Related Disorders

Received Date: 20 March 2017 Revised Date:

14 June 2017

Accepted Date: 24 June 2017

Please cite this article as: Bologna M, Suppa A, Di Stasio F, Conte A, Fabbrini G, Berardelli A, Neurophysiological studies on atypical parkinsonian syndromes, Parkinsonism and Related Disorders (2017), doi: 10.1016/j.parkreldis.2017.06.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

NEUROPHYSIOLOGICAL STUDIES ON ATYPICAL PARKINSONIAN SYNDROMES Matteo Bologna,1-2 Antonio Suppa,1-2 Flavio Di Stasio,2 Antonella Conte,1-2

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Giovanni Fabbrini1-2 and Alfredo Berardelli1-2 1

Department of Neurology and Psychiatry, Sapienza University of Rome, Italy 2

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Neuromed Institute IRCCS, Pozzilli (IS), Italy

Running title: Neurophysiology of atypical parkinsonian syndromes

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Total number of words (Abstract): 169

Total number of words (excluding References): 4585

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Total number of tables/figures: 5

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Corresponding Author: Prof. Alfredo Berardelli

Department of Neurology and Psychiatry and Neuromed Institute IRCCS, Pozzilli (IS), Italy “Sapienza” University of Rome Viale dell’Università 30 00185 Rome, Italy Phone and fax: +390649914700 e-mail:[email protected] 1

ACCEPTED MANUSCRIPT ABSTRACT There have been a relatively large number of experimental investigations using neurophysiological techniques in patients with atypical parkinsonian syndromes (APs), including progressive supranuclear palsy, cortico-basal syndrome and multiple system

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atrophy. Earlier studies focused on the startle, blink and trigemino-cervical reflexes and showed several brainstem abnormalities. Studies using transcranial magnetic stimulation have revealed a number of abnormalities in primary motor cortex and inter-hemispheric

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connectivity. More recent studies have highlighted the role of cerebellar dysfunction and have reported altered movement kinematics. Neurophysiological abnormalities in APs

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reflect degeneration or functional changes at multiple brain levels. In the majority of cases, APs share common abnormalities even though some neurophysiological changes differ among the various APs. Evidence of a correlation between neurophysiological abnormalities and clinical signs and symptoms in APs is limited. This paper provides an

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update on the results of experimental investigations using neurophysiological techniques in APs and also reviews similarities and differences between APs and Parkinson’s disease.

discussed.

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The potential role of neurophysiological abnormalities in the clinical context of APs is also

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Key words: atypical parkinsonism, progressive supranuclear palsy, cortico-basal degeneration, multiple system atrophy.

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ACCEPTED MANUSCRIPT Abbreviations: atypical parkinsonian syndromes (APs), central motor conduction time (CMCT), cerebellar-brain inhibition (CBI), cortico-basal degeneration (CBD), cortico-basal syndrome (CBS), continuous theta burst stimulation (cTBS), cortical silent period (CSP), eye-blink classical conditioning (EBCC), electromyography (EMG), gamma-aminobutyric

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(GABA), intermittent theta burst stimulation (iTBS), input output (I/O), intracortical

facilitation (ICF), ipsilateral silent period (iSP), long-term depression (LTD), long-term potentiation (LTP), motor evoked potential (MEP), multiple system atrophy (MSA), primary

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motor cortex (M1), paired associative stimulation (PAS), progressive supranuclear palsy (PSP), resting motor threshold (RMT), short-interval intracortical inhibition (SICI), short-

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latency afferent inhibition (SAI), transcranial magnetic stimulation (TMS).

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ACCEPTED MANUSCRIPT INTRODUCTION Atypical parkinsonian syndromes (APs) include progressive supranuclear palsy (PSP), cortico-basal degeneration (CBD) and multiple system atrophy (MSA) [1-8]. PSP and CBD

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are pathologically characterized by widespread hyper-phosphorylated tau-protein deposition as well as formation of tufted astrocytes and globoid-shaped neurofibrillary tangles (PSP) and astrocytic plaques (CBD) in several brain areas [6,8,9]. While the extent of brainstem atrophy is greater in PSP than in CBD, atrophy in cortical and basal ganglia

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regions is prominent in CBD [10-15]. Differently, the pathological hallmark of MSA is an

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high density α-synuclein deposition in the form of glial cytoplasmic inclusions in oligodendroglia with prominent atrophy in brainstem, basal ganglia and cerebellum [8,1618]. Owing to the varying and heterogeneous distribution of the pathological changes in multiple brain areas, APs are characterized by a combination of parkinsonism and clinical signs and symptoms of other types [1,3,7,19-21]. Clinically, PSP is characterized by

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parkinsonism, supranuclear gaze palsy, postural instability and early falls which may manifest with different subtypes. Differently, the classic clinical presentation of CBD is the

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corticobasal syndrome (CBS), which implies parkinsonism, dystonia, myoclonus, cortical sensory loss, ideomotor apraxia, alien-limb phenomena with a characteristically

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asymmetrical distribution, and additional cognitive and behavioural impairment. Finally, MSA manifests with a variable combination of parkinsonian, cerebellar, autonomic and pyramidal signs [1,3,7,19-21]. A relatively large number of neurophysiological studies have been conducted on APs over the last three decades and have led to a better understanding of the pathophysiological mechanisms of APs [1,22,23]. Several issues are, however, still unsolved. For example, it is still not clear to what extent the different neurophysiological abnormalities observed in APs are disease specific. Another important issue concerns the possible relationship 4

ACCEPTED MANUSCRIPT between neurophysiological abnormalities and clinical signs in APs. Clarifying these issues might help to gain a better understanding of the relationship between neurophysiological abnormalities and the underlying pathology of APs and their role in generating the clinical

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features in these conditions. In the present paper, we reviewed the main experimental neurophysiological studies investigating the pathophysiology of the most common forms of APs including PSP, CBS and MSA. We did not discuss the results of studies in other less common APs. Also, we

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did not discuss neurophysiological techniques commonly used for clinical purposes,

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including testing of autonomic nervous system or electromyography of the rectal sphincter muscle which have been reviewed elsewhere [22]. We first briefly review the physiological background of the various techniques used in neurophysiological investigations in patients with PSP, CBS and MSA. We then highlight the pathophysiological relevance of the abnormalities detected and the similarities and differences between the various APs and

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between APs and Parkinson’s disease (PD). Lastly, we discuss the possible clinical implications of the neurophysiological abnormalities observed in APs, including their

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relationship with clinical features, the role they may play in the differential diagnosis of the

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disease and in the evaluation of its progression.

BRAINSTEM REFLEXES

Physiological background The startle reflex is an electromyographic (EMG) response that can be recorded in different body parts after an unexpected acoustic stimulus [24] or following electrical stimulation of the median nerve, i.e. somesthetic startle reaction [23-25]. The latencies to onset of the EMG responses in the muscles of the face, trunk and upper and lower limbs 5

ACCEPTED MANUSCRIPT point to a common origin of this reflex in the pontine reticular formation, which integrates inputs from different modalities, and the subsequent conduction up the brainstem and down the spinal cord through slowly conducting pathways [23-25]. The size of the startle

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responses and their habituation are measures of brainstem excitability [23-25]. The trigeminal blink reflex is characterized by an early component (R1) in the orbicularis muscle ipsilateral to the stimulated side, which is mediated by an oligosynaptic pontine circuit, and a bilateral late component in the medullary reticular area (R2), which is

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mediated by a polysynaptic circuit of brainstem interneurons [26-31]. Measurements of the

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R1 and R2 latencies reflects the conductivity of brainstem pathways, whereas stimulation techniques based on pairs of stimuli allow to investigate the R2 recovery cycle, which reflects the excitability of the brainstem circuits [27,28,30].

Trigemino-cervical reflexes are short-latency EMG responses in the muscles of the neck

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and in the proximal muscle of the upper limbs evoked by the electrical stimulation of the supraorbital, infraorbital or mental branch of the trigeminal nerve [32-35]. Trigeminocervical reflexes are mediated by nociceptive afferents and polysynaptic brainstem

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PSP

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pathways converging on upper and lower cervical spinal cord motor neurons [32-35].

The startle reflex is consistently reduced in PSP, both in terms of the muscle recruitment pattern and EMG response amplitude. The latency to onset of the earliest EMG response to acoustic startling stimuli is delayed, with few muscles being activated. The startle reflex can be reduced or absent, with more severe abnormalities being observed in Richardson syndrome than in other PSP subtypes (PSP-parkinsonism and primary progressive freezing of gait) [36-41]. Patients with PSP also display a functional involvement of circuits that mediate the somesthetic startle reaction [25]. 6

ACCEPTED MANUSCRIPT Studies on the trigeminal blink reflex in patients with PSP have consistently shown normal R1 and R2 latencies [25,41,42]. By contrast, the R2 recovery cycle is reported to be abnormally enhanced [25,43] or normal [44,45].

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The trigemino-cervical reflexes are abnormally reduced or absent in a high proportion of PSP patients [41,46], (Table 1). CBS

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A limited amount of evidence is available for the neurophysiological assessment of

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brainstem reflexes in patients with CBS. The amplitude and latency of the facial EMG response to somatosensory startling stimuli is reported to be normal in CBS patients [25]. Valls-Solè et al. [25] observed no significant abnormality in the latency or amplitude of blink-reflex responses in CBS. Moreover, brainstem excitability, as assessed by the R2

[25], (Table 1).

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MSA

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recovery cycle does not significantly differ between patients with CBS and healthy controls

The auditory startle reflex is either normal or abnormally enhanced in MSA in terms of an

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increased response probability, shortened onset latency, enlarged response magnitude and decreased habituation [38,47]. The enhanced startle reflex in MSA is more evident in patients with MSA-P than in those with MSA-C [48]. Also, the somesthetic startle reaction to peripheral electrical stimulation is normal in MSA [25]. Studies on the R2 recovery cycle have also revealed enhanced brainstem excitability in MSA [49-51]. Lastly, the trigemino-cervical reflexes are clearly detectable in MSA-P [52], (Table 1).

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ACCEPTED MANUSCRIPT TRANSCRANIAL MAGNETIC STIMULATION (TMS) STUDIES Physiological background TMS is one of the tools used most widely for the neurophysiological assessment of cortical

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motor areas [53-62]. Single-pulse TMS is used to measure the central motor conduction time (CMCT) and corticospinal excitability (resting motor threshold - RMT). Other

parameters, such as the cortical silent period (CSP), short-interval intracortical inhibition

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(SICI) and intracortical facilitation (ICF), measure the excitability of cortical inhibitorygamma-aminobutyric (GABA)-ergic and excitatory-glutamatergic interneurons [53-62].

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Short-latency afferent inhibition (SAI) reflects the excitability of cholinergic interneurons [63,64]. TMS techniques also yield measurements of connectivity between different areas. TMS protocols based on repetitive TMS (rTMS), including intermittent or continuous thetaburst stimulation (iTBS and cTBS), induce changes in M1 excitability resembling the long-

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term potentiation (LTP) and long-term depression (LTD)-like plasticity [65,66]. Paired associative stimulation (PAS) combines repeated electrical stimuli of the peripheral nerve and TMS over the contralateral M1 at specific interstimulus intervals. PAS25 is known to

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PSP

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elicit LTP-like plasticity, while PAS10 induces LTD-like plasticity of M1 [67,68].

Earlier studies revealed CMCT abnormalities in a proportion of PSP patients, especially those characterized by a longer disease duration [69-71]. More recent studies on PSP have revealed excitability changes of M1. Patients display enhanced MEP amplitudes at rest, a steeper stimulus-response (input-output or I/O) curve, reduced SICI, normal ICF [72-74] and SAI [74,75]. PSP patients display abnormally reduced transcallosal inhibition, as tested by the ipsilateral silent period (iSP), which indicates the involvement of inter-

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ACCEPTED MANUSCRIPT hemispheric fibres in this condition with more severe abnormalities being observed in Richardson syndrome that in patients with PSP-parkinsonism [76], (Table 2). Recent evidence also demonstrates altered M1 plasticity in PSP [73,77] (Table 2).

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CBS MEPs in some patients are virtually un-recordable and typically polyphasic in shape [78,79]. Early studies found increased RMT and a flattened I/O curve, which point to

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reduced M1 excitability in CBS [72,78]. Further studies reported a decreased SICI [72,80-

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82] and shortened CSP in CBS patients, which suggest altered intracortical inhibition [72,78,83,84]. Single-pulse TMS has also detected a shorter iSP [72,85], which reflects the loss of inter-hemispheric inhibitory connections [72,85].

Using TBS in patients with probable CBS, Suppa et al. [79] identified patients with different

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response patterns. When TBS was applied over M1 contralateral to the limb manifesting parkinsonism, all CBS patients displayed reduced responses to TBS. By contrast, when TBS was delivered over M1 contralateral to the limb manifesting parkinsonism and other

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motor and non-motor symptoms, the response to TBS differed according to the patients’ specific clinical features [79], (Table 2). A subgroup of CBS patients displayed low M1

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excitability possibly due to cortico-spinal neuronal loss. Another subgroup of patients manifesting parkinsonism and other motor symptoms was characterized by reduced responses to TBS, whereas a third subgroup of patients manifesting predominantly nonmotor symptoms exhibited abnormally high responses to TBS [79], (Table 2). MSA Various studies have reported a prolonged CMCT [70,71,86,87]. When M1 excitability was tested by means of paired-pulse techniques, SICI was found to be reduced whereas ICF 9

ACCEPTED MANUSCRIPT was normal [72,88,89]. The observation of a longer CSP in MSA provides further evidence of abnormal M1 excitability in this condition [71,72]. Löscher et al. [90] examined the effects of the 5Hz-rTMS on MEP amplitude and CSP

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duration in MSA-P. The reduced response to 5Hz-rTMS observed in this condition points to cortical abnormalities that may reflect altered short-term plasticity mechanisms in M1. More recently, a study designed to test long-term M1 plasticity in MSA patients revealed reduced responses to both iTBS and cTBS protocols in both MSA-P and MSA-C patients

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[89]. Lastly, Kawashima et al. [91] observed decreased PAS25-induced plasticity in M1 in

STUDIES ON CEREBELLUM

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Physiological background

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MSA-P patients, (Table 2).

The neurophysiological assessment of the cerebellum and its projections to the motor cortical areas can be performed by using the cerebellar-brain inhibition (CBI), technique,

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i.e. cerebellar conditioning stimuli inhibit the amplitude of MEP elicited by single-pulse TMS

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of M1 and recorded from the contralateral hand muscle [92,93]. The study of eye-blink classical conditioning (EBCC) reliably assesses cerebellar function [94,95]. EBCC is a form of associative motor learning in which paired presentation of a conditioned auditory tone and of an unconditioned electrical stimulus delivered to the supraorbital nerve results in a conditioned eye blink response. The cerebellar cortex, cerebellar nuclei and inferior olives are critical neuroanatomical sites for the acquisition and retention of a conditioned response [96], (Table 3). PSP 10

ACCEPTED MANUSCRIPT TMS studies indicate that the CBI, i.e. the inhibitory effects of single-pulse TMS over the cerebellum on MEPs elicited by TMS over the contralateral M1, is reduced in PSP patients [74,97]. The EBCC is also markedly impaired in PSP patients [44], (Table 3).

No studies have assessed CBI or EBCC in patients with CBS.

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MSA

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CBS

Although no studies have yet investigated CBI in MSA, a neurophysiological study

patients with MSA [45], (Table 3).

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MOVEMENT STUDIES

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designed to investigate EBCC has provided evidence of abnormal cerebellar circuits in

Physiological background

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Although bradykinesia is one of the cardinal motor sign in APs, surprisingly few neurophysiological studies have objectively assessed upper limb and finger movements in

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these conditions. By contrast, a larger number of kinematic studies have objectively assessed oculomotor abnormalities in APs, including some on eye and eyelid movements. As eye movement abnormalities in APs are widely acknowledged and have been discussed in detail elsewhere [98-100], they will not be discussed further here. PSP When Ling et al. [101] kinematically assessed repetitive finger tapping in PSP patients, they found a specific pattern of ‘hypokinesia without decrement’. Another kinematic study 11

ACCEPTED MANUSCRIPT designed to investigate repetitive finger movement in PSP patients showed that the tapping movement tended to be slower while the movement amplitude was normal [102]. One of the most consistent eyelid movement abnormalities in PSP is a marked decrease

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in the spontaneous blink rate [43,103-107]. Other eyelid movement abnormalities in PSP are slowed closing and opening phases as well as a longer inter-phase pause duration during voluntary blinking and a number of kinematic abnormalities in reflex blinking [43],

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(Table 4).

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CBS

Leiguarda et al. [84], described the kinematic features of apraxic movements during an explorative task involving manipulative fingers movements. The analysis disclosed delayed initiation of the movement and slowed, distorted and fragmented finger movements that revealed a lack of inter-finger coordination, (Table 4). No study has yet assessed blinking

MSA

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kinematics in CBS patients.

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When Djurić-Jovičić et al., [108] assessed the kinematics of finger tapping in MSA-P, they

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found a progressive reduction in movement amplitude when these patients performed repetitive movements, i.e. the sequence effect. Another movement study by Bologna et al., [51] focused on the kinematic analysis of blinking in MSA. Both MSA-P and MSA-C patients exhibited a prolonged inter-phase pause (time elapsing between closing and opening phases) during the voluntary blink and reduced spontaneous blinking rate [51]. In addition, the kinematic analysis showed that the opening phase during voluntary and reflex blinking lasted longer in MSA-P than in MSA-C [51], (Table 4).

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ACCEPTED MANUSCRIPT DISCUSSION In this paper, we present a summary of the results of neurophysiological studies that have investigated brainstem circuits, excitability and plasticity of M1, cerebellar function and

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movement studies in patients with APs. These studies provide insights into the pathophysiology of APs. The neurophysiological abnormalities reported also have a

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potential role in the clinical context of APs.

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Mechanisms underlying neurophysiological abnormalities in APs

An abnormally reduced startle reflex in PSP reflects the degeneration of the brainstem structures, particularly of the pontine reticular formation [25,38]. The observation that changes in the startle reflex are worse in Richardson syndrome than in other PSP

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subtypes (PSP-parkinsonism and PSP-pure akinesia with gait freezing) indicates that these abnormalities reflect the severity of the underlying pathological processes in the various PSP subtypes [40,41]. The startle reflex in MSA, which is, unlike that in PSP,

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abnormally enhanced, may reflect brainstem nuclei disinhibition due to the degeneration of supra-segmental structures, including the basal ganglia [38,45]. The observation that the

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enhanced startle reflex is more evident in MSA-P than in MSA-C suggests that these neural structures are involved to varying extents in the two conditions [48]. Another neurophysiological brainstem abnormality in APs is the hyperexcitability of the trigeminal blink reflex. An experimental model developed in parkinsonian animals has shown that the trigeminal blink reflex is modulated by basal ganglia inhibitory projections to the midbrain rostral structures. Namely, the basal ganglia output originating from the SNpr inhibits neurons in the superior colliculus, which in turn excites tonically active neurons of

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ACCEPTED MANUSCRIPT the nucleus raphe magnus; neurons in the nucleus raphe magnus ultimately inhibit spinal trigeminal neurons involved in the trigeminal blink reflex circuits [109,110]. CMCT changes in APs reflect the degeneration of the corticospinal pathway in these

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conditions [69,71], which is consistent with neuroimaging studies and histopathological findings revealing neurodegenerative phenomena in M1, the premotor cortex and SMA [111-114]. TMS studies have also indicated that a loss of M1 inhibition is a common neurophysiological feature of APs that may reflect alterations in GABA-ergic interneurons

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[72,73,79,89]. In keeping with TMS findings, in vivo positron emission tomographic

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imaging in PSP has shown a global reduction in the cerebral distribution of [11C]flumazenil, a ligand that binds to the GABA-A receptor [115]. Post-mortem pathological examinations have also shown a significant neuronal loss of inhibitory interneurons in the M1 of patients with PSP [116]. In CBS, there is also evidence of a correlation between SICI and the degree of M1 atrophy as measured by voxel-based

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morphometry, which points to a pathophysiological relationship between neurodegenerative processes and TMS abnormalities of M1 [114].

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The abnormal increase in MEP amplitude after TBS in PSP patients, which is indicative of abnormal LTP-like plasticity of M1, may reflect the degeneration of inhibitory interneurons

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[73,77,116]. The response to TBS in CBS, unlike that in PSP, depends on the M1 that is stimulated. We tested the M1 contralateral to the ‘less affected’ limb, i.e. the one manifesting parkinsonism alone, and found that TBS elicited reduced responses [79]. These findings may reflect abnormal motor inputs to M1 from the basal ganglia [89]. When, instead, we tested the M1 contralateral to the ‘more affected’ limb, i.e. the one manifesting parkinsonism and other motor and non-motor signs, we observed altered TBS induced after-effects characterized by a high inter-subject variability. In particular, responses to TBS in CBS patients with parkinsonism, myoclonus and dystonia were 14

ACCEPTED MANUSCRIPT reduced [79]. By contrast, responses to TBS in CBS patients with cortical signs (apraxia, cortical sensory deficit and alien limb phenomena) were increased [79], as had previously been observed in patients with PSP [73]. Thus, in contrast to PSP, M1 plasticity abnormalities in patients with parkinsonism, myoclonus and dystonia reflect subcortical as

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opposed to cortical abnormalities. However, besides abnormal motor inputs from the basal ganglia to cortical motor areas, a subgroup of CBS patients might manifest abnormal connections between M1 and non-primary motor, or even non-motor, areas including the

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sensory cortex [117,118]. Reduced LTP/LTD-like plasticity in MSA-P and MSA-C might reflect intrinsic M1 abnormalities or abnormal motor inputs to M1 from the basal ganglia or

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non-primary motor areas. The latter hypothesis fits in well with the impaired cortical motor network reported in MSA patients in neuroimaging studies [119]. The results of studies in the literature point to a varying involvement of the cerebellum in the different APs. In PSP, the lack of CBI is compatible with clinical and pathological

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studies pointing to the involvement of the Purkinje cells, the dentate nucleus and the dentato-thalamo-cortical pathway in this condition [120,121], even in patients without overt

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cerebellar signs [45,97]. The acquisition of conditioned EBCC responses is impaired in patients with PSP and in both clinical subtypes of MSA [44,45]. Altered EBCC is

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suggestive of neurodegenerative processes in the deep cerebellar nuclei and inferior olive [94-96]. Interestingly, MSA patients may display EBCC abnormalities even when they are clinically characterized by parkinsonian features (MSA-P) rather than by cerebellar signs, thereby pointing to a subclinical cerebellar involvement in MSA-P [45]. The neurophysiological findings are in agreement with the results of histopathological [17] and neuroimaging studies [122-124] that demonstrate cerebellar abnormalities in MSA-C and in MSA-P.

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ACCEPTED MANUSCRIPT In PD bradykinesia describes the slowness of voluntary movement but also refers to low amplitude movements (hypokinesia) and a progressive reduction in speed and amplitude during movement repetition (sequence effect), [125-131]. The few studies that have assessed the features of bradykinesia in APs show that there is no sequence effect in PSP

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patients during repetitive finger tapping, a finding believed to reflect severe hypokinesia due to the marked involvement of the motor control system in this condition [101,108], whereas patients with MSA-P do display a progressive reduction in speed during repetitive

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finger movements [108]. Movement studies on CBS have suggested that apraxia might reflect the altered integration of somatosensory afferent inputs in the fronto-parietal

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cortices, which also leads to cortical sensory loss or more complex features such as alien limb phenomena. Grasping and manipulative movements during an explorative task require knowledge of the spatial location and intrinsic properties of the object as well as the ability to generate independent fingers movements [132], both of which are integrated

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in a range of fronto-parietal cortical circuits. Neuropathological studies on CBS have revealed widespread and asymmetric cortical degeneration in the frontal regions and sensorimotor, superior and inferior parietal cortices [133]. Hence, alterations in the

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intracortical inhibitory and sensory-motor circuits located in the fronto-parietal circuits

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might contribute to abnormal finger movement control and apraxia in CBS. The reduced spontaneous blinking rate in PSP and MSA reflects the reduced central dopaminergic tone or primary degeneration in other cerebral structures, including the frontal lobe areas and the brainstem, that are thought to be involved in generating the spontaneous blinking rate [43,105,134,135]. Voluntary blinking in PSP patients is characterized by slowed closing and opening phases and an increased inter-phase pause [43]. We recently observed that slowed switching between the closing and opening voluntary blinking phase in PSP is related to neurodegenerative processes in the basal 16

ACCEPTED MANUSCRIPT ganglia, [43,106]. In addition, the kinematic abnormalities of reflex blinking in PSP and MSA [43,51] may reflect the neurodegenerative processes of pre-motor structures and

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motor effectors at the brainstem level [136], (Table 4).

Similarities and differences between the neurophysiological abnormalities in APs Common neurophysiological abnormalities in APs include prolonged CMCT [69-71,86,87]

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and loss of M1 inhibition [71-74,78,83,84,88,89], (Figure 1). Cerebellar abnormalities, as

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assessed by EBCC, and various blinking abnormalities, including the trigeminal blink reflex hyperexcitability [25,43,49-51], the spontaneous blinking rate reduction and other abnormalities of blinking kinematics [43-45,51] might be impaired in both PSP and MSA (Figure 1). These similarities suggest that in APs there is a similar involvement of multiple brain areas including the brainstem, M1 and cerebellum and basal ganglia, despite

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differences in their underlying pathology.

An abnormally reduced startle reflex is a specific abnormality of PSP [36-41]. The

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abnormal increase in MEP amplitude after TBS in PSP patients indicates enhanced M1plasticity [73], which is overall in contrast to the observation of reduced M1 plasticity in

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MSA and CBS patients [79,89]. Movement studies that have assessed the features of bradykinesia in APs suggest that the lack of a sequence effect during repetitive finger tapping is a specific feature of PSP [101]. These differences suggest a specific pattern of brainstem and cortical pathology in PSP than in CBS and in MSA (Figure 1). Differently from PSP, CBD and MSA, only a limited number of experimental neurophysiological studies have been conducted in other APs, including Lewy body dementia [137]. Major findings in patients with Lewy body dementia include abnormal

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ACCEPTED MANUSCRIPT latency of the R2 component of the trigeminal blink reflex, reduced startle reflex and SAI but normal intracortical inhibition [137].

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Similarities and differences between the neurophysiological abnormalities in APs and PD

The neurophysiological abnormalities of APs which also characterize PD include the

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hyperexcitability of the trigeminal blink reflex, spontaneous blinking rate reduction [105]

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and the loss of M1 inhibition [71-74,78,83,84,88,89,138,139].

The major neurophysiological differences between APs and PD include the startle reflex abnormalities [25,36-41,47,48] and the CMCT prolongation [69-71,86,87]. The abnormally enhanced M1-related plasticity in M1 in PSP [73] differ from the loss of M1 plasticity in PD

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[139,140]. The abnormally reduced M1 plasticity in M1 in similar in MSA and in PD [89,139,140]. However the dopaminergic therapy restores the lack of PAS-related plasticity of M1 in PD but not in MSA-P [91]. These results overall support the hypothesis that

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APs.

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different mechanisms possibly underlie the abnormalities of M1 plasticity in the various

Cerebellar involvement, as assessed by EBCC examination is another abnormality present in APs but not in PD [45]. APs are characterized by slowness of voluntary movements and in PSP by the lack of a ‘sequence effect’ during repetitive finger tapping [101] which is considered a specific finding in PD [125-131]. Recent observations, however, indicate that the ‘sequence effect’ during repetitive finger tapping is no longer observed in patients with advanced PD [141]. These observations implies that finger movement abnormalities in APs and PD do not necessarily reflect the specific underlying pathology of the diseases

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ACCEPTED MANUSCRIPT [141]. Kinematic studies also indicate more severe voluntary and reflex blinking abnormalities in APs than in those with PD [43,51,105]. The neurophysiological similarities between APs and PD support the hypothesis that a

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number of brain structures are similarly affected by APs and PD despite their different pathology. On the other hand, differences between APs and PD indicate a prominent involvement of brain areas in APs, namely the brainstem reticular formation, the

corticospinal tract and a specific pattern of pathology involving M1 interneurons and

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cerebellar structures.

Clinical implications

There is as yet little evidence of any correlation between neurophysiological abnormalities

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and the clinical manifestations of APs. TMS studies indicates that the lack of interhemispheric inhibitory interactions is related to cognitive abnormalities in PSP (Richardson syndrome), which points to a possible relationship between white matter changes and

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cognitive impairment in this condition [72,76]. Again in PSP, Nardone et al., [75] found that SAI, did not significantly differ between PSP patients and healthy controls thus indicating

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that sub-cortical, rather than cortical cholinergic dysfunction underlies cognitive abnormalities in PSP. In MSA, Celebi et al. [142] found that cognitive impairment in patients parallels SAI reduction. Conversely, there is no only limited evidence of any association between neurophysiological findings and the severity of motor signs in APs [72,88]. Kuhn et al., [72] reported no significant correlation between Unified Parkinson's Disease Rating Scale scores and TMS parameters in PSP, CBS and MSA. However, the authors found some correlations between TMS parameters and specific symptoms in PSP (postural instability and supranuclear gaze palsy) and in MSA (severity of pyramidal signs). 19

ACCEPTED MANUSCRIPT Again, Marchese et al., [88] found no significant correlation between the reduction of M1 inhibition and the Unified Parkinson's Disease Rating Scale scores in patients with MSA-P. Moreover, the authors observed M1 inhibition increase after levodopa administration without clinical changes. Future studies are warranted to clarify whether the

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neurophysiological abnormalities of M1 possibly underlie the motor features in APs. Another important clinical implication of neurophysiological studies in APs is the support they provide in the clinical diagnosis and in distinguishing between them. Morita et al., [71]

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observed that various TMS measures can differentiate PSP, MSA and PD in the early

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disease stages. In addition, other studies on MEP [70]; trigemino-cervical reflexes [52], EBCC [45]; spontaneous blinking [104,107] and finger tapping [101,102,108] suggest a possible role of neurophysiological testing in differentiating the various APs. Owing to the relatively low sensitivity of the majority of neurophysiological findings in APs, and to the lack of post mortem confirmation of APs diagnosis in the various studies performed, it is

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not yet possible to conclude that neurophysiological techniques are useful in the differential diagnosis of APs.

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Limited evidence suggests that some neurophysiological abnormalities may be useful in the longitudinal assessment of patients with APs and disease progression [39,73]. Gironell

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e al., [39] performed a 26 months longitudinal study on the startle reflex in early stages of APs. The authors found that the assessment of the startle reflex had high predictive value in the diagnosis of these conditions. Conte et al., [73] performed a 12 months follow-up study to investigate possible longitudinal changes of enhanced M1 plasticity in PSP. The authors observed that the enhancement of M1 plasticity in PSP parallels the disease progressions, as assessed by clinical examination. These studies overall indicate that the longitudinal assessment of APs, using neurophysiological techniques, might provide useful

20

ACCEPTED MANUSCRIPT surrogate biomarkers. Further studies, however, are warranted to better delineate this issue.

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CONCLUSIONS The growing body of neurophysiological studies has revealed abnormalities at multiple levels of the central nervous system reflecting degeneration or functional changes in the

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specific brain areas underlying the various parameters tested. In the majority of cases, the

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various APs share a common pattern of neurophysiological abnormalities, thereby ruling out any distinct relationship with the underlying pathology. The neurophysiological assessment of APs may nevertheless lead to the detection of specific abnormalities in some cases, such as an abnormally low startle reflex or enhanced M1 plasticity in PSP, that are more closely related to the pathological substrate of the disease. Future studies

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should better delineate the reliability and the specificity of neurophysiological abnormalities in APs, also in comparison to PD, as well as their relationship with clinical features, which are still largely unclear. Other potential applications of neurophysiological techniques for

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clinical purposes in APs include making a differential diagnosis between the various forms,

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especially in cases whose classification is uncertain, and evaluating disease progression.

21

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FIGURE LEGENDS

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Figure 1. Diagram summarizing the similarities (overlap areas) and differences of the major neurophysiological findings in progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA). Shown are the most common

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abnormalities found in the three conditions. Note that not all the neurophysiological

techniques have been applied in the three APs. The acoustic startle reflex, eye-blink

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classical conditioning (EBCC) and movement studies (on finger tapping and blinking) have been performed in PSP and MSA but not in CBS. M1 inhibition refers to the evaluation of short-latency intracortical inhibition. M1 plasticity refers to the after effects of theta-burst simulation. Note that M1 plasticity in CBS is variable, enhanced M1 plasticity was only

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found in a subgroup of patients manifesting predominantly non-motor symptoms. Blinking abnormalities refer to hyperexcitability of trigeminal blink reflex as assessed by the recovery cycle of the R2 component, spontaneous blinking rate reduction and various

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kinematic abnormalities of voluntary and reflex blinking. Sequence effect indicates the progressive reduction of movement amplitude during finger tapping. Primary motor cortex

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(M1); central conduction motor time (CMCT).

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ACCEPTED MANUSCRIPT

CONTRIBUTORS MB: conception and design of the study, acquisition of data, interpretation of data, drafting

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the article, final approval of the submitted version of the manuscript

AS: conception and design of the study, acquisition of data, interpretation of data, drafting the article, final approval of the submitted version of the manuscript.

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FDS: acquisition of data, interpretation of data, drafting the article, final approval of the submitted version of the manuscript.

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AC: interpretation of data, revising the article for important intellectual content, final approval of the submitted version of the manuscript

GF: interpretation of data, revising the article for important intellectual content, final approval of the submitted version of the manuscript.

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AB: conception and design of the study, interpretation of data, revising the article for

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important intellectual content, final approval of the submitted version of the manuscript.

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ACKNOWLEDGMENT This research did not receive any specific grant from funding agencies in the public,

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commercial, or not-for-profit sectors.

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ACCEPTED MANUSCRIPT Table 1. Neurophysiological studies that have investigated the role of the brainstem in atypical parkinsonian syndromes (APs). APs

Technique

Major findings

[36] Vidailhet et al.,1992

PSP

startle reflex (auditory)

delayed and reduced response

[37] Rothwell et al.,1994

PSP

startle reflex (auditory)

absent response

[38] Kofler et al., 2001

PSP

startle reflex (auditory)

delayed and reduced response

[39] Gironell et al., 2003

PSP

startle reflex (auditory)

delayed and reduced response

[40] Williams et al.,2008

PSP

startle reflex (auditory)

reduced response

[41] Kızıltan et al., 2013

PSP

startle reflex (auditory)

reduced response

[25] Valls-Solè et al.,1997

PSP

startle reflex (somesthetic)

reduced response

[25] Valls-Solè et al.,1997

PSP

trigeminal blink reflex

normal R1 and R2 latencies

[42] Bonanni et al., 2007

PSP

trigeminal blink reflex

normal R1 and R2 latencies

[41] Kızıltan et al., 2013

PSP

trigeminal blink reflex

[25] Valls-Solè et al.,1997

PSP

trigeminal blink reflex

[44] Sommer et al.,2001

PSP

trigeminal blink reflex

[43] Bologna et al., 2009

PSP

trigeminal blink reflex

enhanced R2 recovery cycle

[45] von Lewinski et al.,2013

PSP

trigeminal blink reflex

normal R2 recovery cycle

[46] Bartolo et al.,2008

PSP

trigemino-cervical reflex

reduced response

[41] Kızıltan et al., 2013

PSP

trigemino-cervical reflex

reduced response

[25] Valls-Solè et al., 1997

CBS

startle reflex (somesthetic)

normal response

[25] Valls-Solè et al., 1997

CBS

trigeminal blink reflex

normal latency and amplitude

[47] Valldeoriola et al., 1997

MSA

startle reflex (auditory)

enhanced response

[38] Kofler et al., 2001

MSA

[48] Kofler et al. 2003

MSA

[25] Valls-Solè et al., 1997

MSA

[49] Kagohashi et al., 2004

MSA

[50] Mascia et al., 2005

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enhanced R2 recovery cycle

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normal R2 recovery cycle

enhanced response

startle reflex (auditory)

enhanced response

startle reflex (somesthetic)

normal response

trigeminal blink reflex

enhanced R2 recovery cycle

MSA

trigeminal blink reflex

enhanced R2 recovery cycle

MSA

trigeminal blink reflex

enhanced R2 recovery cycle

MSA

trigemino-cervical reflex

detectable response

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[52] Serrao et al., 2011

normal R1 and R2 latencies

startle reflex (auditory)

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[51] Bologna et al., 2014

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[ref.N] Study

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ACCEPTED MANUSCRIPT Table 2. Neurophysiological studies on primary motor cortex excitability and plasticity in atypical parkinsonian syndromes (APs). APs

Technique

Major findings

[69] Abbruzzese et al,1991

PSP

single pulse TMS

Prolonged CMCT

[70] Abbruzzese et al,1997

PSP

single pulse TMS

Prolonged CMCT

[72] Kühn et al.,2004

PSP

single pulse TMS

increased MEP ampl., prolonged iSP and CSP

[73] Conte et al.,2012

PSP

single pulse TMS

Increased I/O MEP

[72] Kühn et al.,2004

PSP

paired pulse TMS

reduced SICI, normal ICF

[73] Conte et al.,2012

PSP

paired pulse TMS

reduced SICI, normal ICF

[74] Brusa et al.,2014

PSP

paired pulse TMS

reduced SICI, normal ICF

[75] Nardone et al.,2005

PSP

single pulse TMS plus nerve stim.

normal SAI

[74] Brusa et al.,2014

PSP

single pulse TMS plus nerve stim.

normal SAI

[76] Wittstock et al.,2013

PSP

single pulse TMS (during contraction)

[73] Conte et al.,2012

PSP

iTBS/cTBS

[77] Bologna et al.,2017

PSP

iTBS

[83] Lu et al., 1998

CBS

single pulse TMS

reduced MEP amplitude and CSP duration

[78] Valls-Solé et al., 2001

CBS

single pulse TMS

reduced MEP amplitude and CSP duration

[72] Khun et al.,2004

CBS

single pulse TMS

reduced MEP amplitude and CSP duration

[80] Hanajima et al.,1996

CBS

paired pulse TMS

reduced SICI

[81] Okuma et al.,2000

CBS

paired pulse TMS

reduced SICI

[72] Khun et al.,2004

CBS

paired pulse TMS

reduced SICI, normal ICF

[82] Pal et al.,2008

CBS

single pulse TMS

normal/ incr. RMT, reduced iSP, CSP and I/O

[84] Leiguarda et al.,2003

CBS

single pulse TMS

reduced CSP (apraxic limb)

[85] Trompetto et al.,2003

CBS

single pulse TMS (during contraction)

reduced iSP duration

[72] Kuhn et al.,2004

CBS

single pulse TMS (during contraction)

reduced iSP duration

[82] Pal et al.,2008

CBS

paired pulse TMS

reduced SICI, normal ICF

[79] Suppa et al.,2016

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enhanced MEP facilitation

CBS

iTBS/cTBS (park. hemisphere)

reduced LTP/LTD

CBS

iTBS/cTBS (park. plus hemisphere)

reduced or increased LTP/LTD

MSA

single pulse TMS

prolonged CMCT

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[86] Cruz Martinez et al.,1995

reduced iSP in PSP-P, normal iSP in RS enhanced MEP facilitation

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[79] Suppa et al.,2016

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[ref.N] Study

[70] Abbruzzese et al.,1997

MSA

single pulse TMS

prolonged CMCT

[72] Kühn et al.,2004

MSA

single pulse TMS

increased MEP ampl., prolonged iSP and CSP

[71] Morita et al., 2008

MSA

single pulse TMS

prolonged CMCT

[142] Celebi et al., 2001

MSA

single pulse TMS plus nerve stim.

reduced SAI

[88] Marchese et al., 2000

MSA

paired pulse TMS

reduced SICI, normal ICF

[72] Kühn et al.,2004

MSA

paired pulse TMS

reduced SICI, normal ICF

[89] Suppa et al.,2014

MSA

paired pulse TMS

reduced SICI, normal ICF/SICF

[87] Eusebio et al., 2007

MSA

triple-pulse TMS

prolonged CMCT

[90] Löscher et al., 2007

MSA

5Hz rTMS

reduced response

[91] Kawashima et al., 2013

MSA

PAS25

reduced MEP modulation

[89] Suppa et al.,2014

MSA

iTBS/cTBS

reduced MEP modulation

ACCEPTED MANUSCRIPT Table 3. Neurophysiological studies that have investigated cerebellar function in atypical parkinsonian syndromes (APs). APs

Technique

Major findings

[97] Shirota et al., 2010

PSP

cerebellar-brain inhibition

reduced inhibition of M1

[74] Brusa et al., 2014

PSP

cerebellar-brain inhibition

reduced inhibition of M1

[44] Sommer et al., 2001

PSP

eyeblink classical conditioning

reduced acquisition of conditioned responses

[45] von Lewinsky et al., 2013

PSP

eyeblink classical conditioning

reduced acquisition of conditioned responses

[45] von Lewinsky et al., 2013

MSA

eyeblink classical conditioning

reduced acquisition of conditioned responses

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ACCEPTED MANUSCRIPT Table 4. Neurophysiological studies that have investigated the voluntary movement kinematics in atypical parkinsonian syndromes (APs). APs

Movement analyzed

Major findings

[101] Ling et al.,2012

PSP

finger tapping

reduced movement amplitude without decrement

[102] Stegemöller et al.,2015

PSP

finger tapping

slowed movement velocity, normal movement amplitude

[108] Djurić-Jovičić et al.,2016

PSP

finger tapping

reduced movement amplitude without decrement

[43] Bologna et al.,2009

PSP

voluntary blinking

slowed closing and opening phases and interphase pause duration

[84] Leiguarda et al.,2003

CBS

finger movement (apraxic hand)

delayed initiation, distorted and fragmented finger movements

[108] Djurić-Jovičić et al.,2016

MSA

finger tapping

sequence effect

[51] Bologna et al.,2014

MSA

voluntary blinking

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[ref.N] Study

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slowed opening phase and inter-phase pause duration

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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT HIGHLIGHTS •

Neurophysiological studies allow to detect several abnormalities in atypical

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parkinsonian syndromes •

The abnormalities reflect degeneration or functional changes at multiple brain levels

•

Some specific abnormalities are likely related to the pathological substrate of the

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Future studies should better delineate the clinical implications of neurophysiology in

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patients

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•

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disease

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