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Long Trace Eyeblink Conditioning Is Largely Preserved in Essential Tremor

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Long Trace Eyeblink Conditioning Is Largely Preserved in Essential Tremor The Cerebellum (2019) 18:67–75 https://doi.org/10.1007/s12311-018-0956-z ORIGINAL PAPER Long Trace Eyeblink Conditioning Is Largely Preserved in Essential Tremor Kasja Solbach1 & Simba-Joshua Oostdam1 & Martin Kronenbuerger2,3 & Dagmar Timmann1 & Marcus Gerwig1 Published online: 18 June 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract The cerebellum and the prefrontal cortex are assumed to play a role in the pathophysiology of essential tremor (ET). Trace eyeblink conditioning with a long interstimulus interval relies on an intact function of the hippocampus, prefrontal cortex (PFC), and, although marginally, of the cerebellum. The aim of the present study was to evaluate whether long trace eyeblink conditioning is impaired in patients with ET. In 18 patients with ET and 18 controls, a long trace conditioning paradigm was applied. Following 100 paired conditioned response-unconditioned response trials, 30 con- ditioned response alone trials were given as extinction trials. The degree of tremor and the presence of accompanying cerebellar signs were determined based on clinical scales. The acquisition of conditioned eyeblink responses was not impaired in the group of all patients compared to controls (mean total incidences of conditioned responses in patients 23.3 ± 14.5%, in controls 24.1 ± 13.9%; P = 0.88). In the subgroup of six patients with cerebellar signs, incidences of conditioned responses were numerically but not significantly lower (16.4 ± 9.9%) compared to patients without cerebel- lar signs (26.8 ± 15.5%; P = 0.16). Trace eyeblink conditioning with a long interstimulus interval was not impaired in subjects with ET. Patients with clinical cerebellar signs presented slightly reduced conditioning. Areas of the PFC contributing to trace eyeblink conditioning appear less affected in ET. Future studies also using a shorter trace interval should include a larger group of subjects in all stages of ET. Keywords Essential tremor . Trace eyeblink conditioning . Cerebellum . Associative learning Introduction [3–6]. There is evidence from clinical, animal, and imaging studies that, besides the cerebellum, the prefrontal cortex Essential tremor (ET) is one of the most prevalent move- (PFC) is involved in the pathophysiology of ET [7–11]. ment disorders [1]. The pathophysiology remains incom- The aim of the current study was to assess prefrontal and pletely understood. There is ongoing debate whether ET is cerebellar involvement in ET using trace eyeblink condition- a more complex degenerative disorder or a reversible func- ing. The acquisition of trace conditioned eyeblink responses tional disturbance of neuronal oscillation [2]. Clinical, neu- strongly depends on the forebrain, i.e., the hippocampal for- roimaging, and post-mortem studies suggest a contribution mation [12–15] and the PFC [16–21], given that the trace of the olivo-cerebellar system in the pathogenesis of ET interval is long enough. Animal studies suggest a role of the cerebellum, i.e., of the deep nuclei as well as the cerebellar cortex [22–25]. However, as revealed by studies in humans, * Marcus Gerwig the cerebellar involvement using a long hippocampus- [email protected] dependent trace interval appears substantially less compared to a shorter trace interval or delay eyeblink conditioning [26, 1 Department of Neurology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany 27]. The PFC might be less involved in longer CS-US inter- vals as has been shown for delay conditioning [28]. We were 2 Department of Neurology, Johns Hopkins University, Baltimore, MD, USA interested if long trace eyeblink conditioning is affected in ET subjects and whether this might be prominent in ET subjects 3 Department of Neurology, University of Greifswald, Ferdinand-Sauerbruch-Strasse, Greifswald, Germany with accompanying clinical signs. 68 Cerebellum (2019) 18:67–75 Methods a more complex form of associative learning. Here, CS and US are separated by a stimulus-free time interval requiring a Subjects Bmemory trace.^ It has to be noted that delay conditioning might also require a Bmemory trace^, because stimuli that are A total of 18 ET subjects (12 male, 6 female; mean age not modified decrease exponentially in their activation of the 56.9 ± 19.2 years, range 23 to 83 years) diagnosed accord- corresponding sensory receptors and pathways. First, ten CS ing to the criteria established by Deuschl et al. [29] and 18 alone and ten US alone trials were presented in an unpaired age- and sex-matched control subjects (10 male, 6 female; and random order, followed by 100 paired CS-US trials and mean age 56.7 ± 10.9 years, range 27 to 74 years) were 30 CS alone trials as extinction trials at the end of the exper- included in the study. Mean duration of tremor in the ET iment. A tone as CS was presented to the right ear, followed group from symptom onset until examination was 20.1 ± by the stimulus-free trace interval of 1000 ms. An air-puff 11.7 years, with a range of 2 to 40 years. The family history wasusedasUS.Intheacquisitionphase,9–10US alonetrials for ET was positive in eight subjects, i.e., in 44.4% with at were interspersed. Surface EMG recordings were taken from least one affected first-degree relative. Nine subjects were orbicularis oculi muscles ipsilaterally to the US with elec- medicated with propranolol for treatment of tremor in ET, trodes fixed to the lower eyelid and to the nasion. Trace con- but none had a dose of more than 1 mg per kg body weight ditioned eyeblink responses were automatically identified which could impede eye blink conditioning [30]. Subjects within the CS-US interval in paired and extinction trials using other centrally acting drugs, e.g., gabapentin or using custom-made software. Responses occurring within primidone were excluded. None of the control subjects the 150 ms interval after CS-onset were considered as reflex- had a history of neurological diseases. All ET and control ive responses to the tone (i.e., alpha-responses) and not con- subjects were naïve for eyeblink conditioning. The study ditioned responses [35]. Trials with spontaneous blinks (SB) was approved by the local ethics committee and written occurring prior to CS onset were excluded from the analysis informed consent was obtained from all subjects. [36]. The investigator (S.J.O) was blinded regarding the par- An experienced neurologist (KS) performed a com- ticipants (ET subjects vs. controls). plete neurological examination. The degree of tremor The total number of paired trials was subdivided into was evaluated using the BClinical Rating Scale for blocks of ten trials each. The number of conditioned Tremor,^ part 1 (CRST, max. score 80) [31]andan responses was expressed as the percentage of trials con- BIntention tremor score^ asdescribedbyHelmchenet taining responses with respect to each block of ten trials al. [5]. To evaluate possible accompanying ataxia symp- (percentage CR-incidence) and the total number of trials toms, the BInternational Cooperative Ataxia Rating (total percentage CR-incidence). Scale^ (ICARS, max. score 100) [32] was used. Three extinction blocks of 10 trials each were administered Six subjects presented with cerebellar signs. Three of them at the end of the experiment. To evaluate extinction effects, (ID 2, 6, and 7 in Table 1) showed intention tremor of both CR-incidence within the last block of paired trials (block 10) upper limbs based on scores of at least two points in an inten- was compared with the last block of extinction trials (extinc- tion tremor score [5, 33]. Further three subjects had postural tion block 3). Moreover, the decline of CR-incidence across instability based on at least two points on the posture and gait the three extinction blocks was analyzed. Analysis of extinc- sub-score of the ICARS [33, 34] (ID 8, 11 and 16 in Table 1). tion was performed only in those subjects who exhibited at The CRST and ICARS were correlated in the patient group least one CR in the first extinction block to ensure a remaining (R =.486,P = 0.041). Controls did not present with abnormal- ability of learning in the paired trials [26, 33]. ities in CRST and ICARS. None of the subjects had clinical Onset and peaktime of CRs in paired trials und URs in signs of brainstem dysfunction, dystonia, or other abnormali- unpaired trials were automatically quantified as outlined ties on clinical examination Clinical characteristics of the ET above (Fig. 1). US onset was set as 0 ms. CR onset and subjects are summarized in Table 1. peaktime were expressed as negative values (prior US onset). Individual values for CR and UR onset and time Trace Eyeblink Conditioning to peak were averaged. EMG peak amplitudes were mea- sured ipsilaterally. It has to be noted that due to method- Details of the trace eyeblink conditioning procedure were ological conditions sizes of peak amplitudes in surface reported previously and are repeated in brief [27]. A long EMG recordings might vary and have to be considered trace interval was used. A conditioned stimulus (CS), such with care [37]. as a tone, is followed by an unconditioned stimulus (US), In each session, the frequency of SB was measured within such as an air-puff delivered close to the eye. In delay condi- 1 min both at the beginning and the end of the experiment. The tioning, the CS and US partly overlap and terminate at the rate of alpha-blinks was analyzed within the 150 ms interval same time. Different from that, trace eyeblink conditioning is after CS onset of 100 paired trials. Cerebellum (2019) 18:67–75 69 Table 1 Patient characteristics ID Sex Age Disease duration Family history CRST Intention ICARS (years) (years) of ET tremor score total of right arm total Posture and part 1 left arm Gait 01 m 23 8 – 60140 02 m 24 24 – 30 4 4 12 0 03 m 32 31 – 20030 04 f 39 19 + 1 0 0 2 1 05 m 61 16 – 70041 06 f 69 29 + 12 3 3 9 0 07 m 63 33 + 15 2 3 9 0 08 f 74 4 – 200113 09 m 55 39 – 40061 10 m 71 11 – 20061 11 m 66 16 – 20053 12 m 69 2 – 11 0 1 6 1 13 m 69 30 – 40031 14 f 25 11 – 80030 15 f 70 5 – 40021 16 m 83 15 + 6 1 1 11 3 17 f 69 40 – 41091 18 m 63 28 – 50051 Assessment of tremor: BClinical Rating Scale for Tremor^ (CRST, part 1); BIntention tremor score^.
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