Introduction
(1) Indicative | Is the physiomarker sufficiently linked to the severity of fluctuating symptoms? |
(2) Individual | Is the physiomarker detectable in every patient and patient-specific if needed? |
(3) Implementable | Is the physiomarker (technically) capable of automatically titrating stimulation? |
Literature search and research synthesis
Study | n Patients/Hemispheres | LFP signal feature | UPDRS items | Medication state | Outcomea |
---|---|---|---|---|---|
Beta-based | |||||
Doyle et al. (2005) [50] | 14/14 | Duration of movement-related spectral power decrease (13–35 Hz) | Total UPDRS-III | On, off | R2 = 0.20 |
14/14 | Amplitude of movement-related spectral power decrease (13–35 Hz) | Total UPDRS-III | On, off | R2 = 0.15 | |
Kühn et al. (2006) [13] | 9/17 | Absolute spectral power within ± 2.5 Hz range around peak (8–35 Hz) | Total hemibody | Levodopa-induced changes | ρ = 0.81 |
9/17 | Absolute spectral power within ± 2.5 Hz range around peak (8–35 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | ρ = 0.84 | |
Ray et al. (2008) [51] | 7/11 | Absolute spectral peak power (8–35 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | ρ = 0.70 |
Kühn et al. (2009) [14] | 30/51 | Absolute spectral power within ± 5.5 Hz range around peak (8–35 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.38 |
Chen et al. (2010) [26] | 12/23 | Lempel-Ziv complexity (13–35 Hz) | Total hemibody | Off | ρ = –0.54 |
12/23 | Lempel-Ziv complexity (13–35 Hz) | Hemibody bradykinesia + rigidity | Off | ρ = –0.53 | |
Pogosyan et al. (2010) [23] | 18/36 | Phase coherence between unilateral contacts (13–35 Hz) | Hemibody bradykinesia + rigidity | Off | R2 = 0.15 |
López-Azcárate et al. (2010) [15] | 14/26 | Normalised spectral peak power (12–20 Hz) | Hemibody bradykinesia + rigidity | Off | ρ = 0.43 |
Özkurt et al. (2011) [16] | 9/17 | Absolute spectral peak power (8–35 Hz) | Hemibody bradykinesia + rigidity | On, off | ρ = 0.33 |
Little et al. (2012) [27] | 18/36 | Coefficient of variation spectral power over time (21–33 Hz) | Hemibody bradykinesia + rigidity | Off | ρ = –0.59 |
10/17 | Coefficient of variation spectral power over time (21–33 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | ρ = –0.66 | |
Hohlefeld et al. (2013) [52] | 10/10 | Imaginary part of coherency between unilateral contacts (10–30 Hz)b | Total UPDRS-III | Levodopa-induced changes | R2 = 0.55 |
Hohlefeld et al. (2014) [53] | 8/8 | Imaginary part of coherency between bilateral contacts (10–20 Hz)b | Total UPDRS-III | Off | R2 = 0.73 |
van Wijk et al. (2016) [18] | 33/65 | Normalised spectral power (13–20 Hz) | Hemibody bradykinesia + rigidity | On, off | R2 = 0.09 |
Neumann et al. (2016) [19] | 63/63 | Normalised spectral power (8–35 Hz)b | Total UPDRS-III | Off | ρ = 0.44 |
West et al. (2016) [21] | 12/21 | Absolute spectral power (13–20 Hz) | Hemibody bradykinesia + rigidity | Off | R2 = 0.39 ρ = 0.66 |
12/22 | Absolute spectral power (13–20 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.40 ρ = 0.56 | |
12/24 | Coherence between unilateral contacts (13–20 Hz) | Hemibody bradykinesia + rigidity | Off | R2 = 0.41 ρ = 0.64 | |
12/24 | Weighted phase lag index between unilateral contacts (13–20 Hz) | Hemibody bradykinesia + rigidity | Off | R2 = 0.31 ρ = 0.58 | |
12/12 | Detrended fluctuation analysis of phase synchrony between bilateral contacts (13–20 Hz)b | Bradykinesia + rigidity | Off | R2 = 0.47 ρ = 0.73 | |
11/11 | Detrended fluctuation analysis of phase synchrony between bilateral contacts (13–20 Hz)b | Bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.33 ρ = 0.83 | |
Beudel et al. (2017) [47] | 39/78 | Normalised spectral peak power (13–30 Hz) | Hemibody bradykinesia + rigidity | Off | ρ = 0.40 |
Neumann et al. (2017) [20] | 12/24 | Normalised spectral power within ± 3 Hz range around peak (13–35 Hz) | Total hemibody | On, off | ρ = 0.25 |
Tinkhauser et al. (2017) [24] | 8/16 | Percentage of beta bursts with long duration | Total hemibody | Off | ρ = 0.55 |
8/16 | Percentage of beta bursts with short duration | Total hemibody | Off | ρ = –0.30 | |
8/16 | Median beta burst duration | Total hemibody | Levodopa-induced changes | ρ = 0.50 | |
Tinkhauser et al. (2017) [25] | 13/16 | Percentage of beta bursts with long duration | Total hemibody | Off | R2 = 0.12 |
13/16 | Percentage of beta bursts with short duration | Total hemibody | Off | R2 = 0.10 | |
Martin et al. (2018) [54] | 13/26 | Normalised spectral peak power (13–35 Hz) | Total hemibody | Off | ρ = 0.50 |
13/26 | Normalised spectral peak power (13–35 Hz) | Hemibody bradykinesia + rigidity | Off | ρ = 0.68 | |
Özkurt et al. (2020) [17] | 14/26 | Nonlinearity of time series (13–30 Hz) | Hemibody tremor | Off | R2 = 0.20 |
14/26 | Normalised spectral power (13–30 Hz) | Hemibody bradykinesia + rigidity | Off | R2 = 0.25 | |
14/26 | Normalised spectral power (13–30 Hz) | Hemibody tremor | Off | R2 = 0.26 | |
Tamir et al. (2020) [22] | 8/12 | Normalised spectral power (13–30 Hz) | Hemibody bradykinesia + rigidity | Off | R2 = 0.36 |
Nie et al. (2021) [55] | 10/10 | Percentage of beta bursts with long durationb | Total UPDRS-III | Off | ρ = 0.74 |
10/20 | Percentage of beta bursts with long duration | Hemibody tremor | Off | ρ = 0.59 | |
10/20 | Percentage of beta bursts with long duration | Hemibody rigidityc | Off | ρ = 0.45 | |
Sure et al. (2021) [56] | 24/44 | Beta burst duration | Hemibody bradykinesia + rigidity | Off | R2 = 0.23 |
Other | |||||
Pogosyan et al. (2010) [23] | 18/36 | Phase coherence between unilateral contacts (8–12 Hz) | Hemibody tremor | Off | R2 = 0.15 |
López-Azcárate et al. (2010) [15] | 14/26 | Normalised spectral peak power (250–350 Hz) | Hemibody bradykinesia + rigidity | Off | ρ = 0.50 |
14/24 | Movement-related changes in spectral peak power (250–350 Hz) | Hemibody bradykinesia + rigidity | Off | R2 = 0.39 | |
14/22 | Phase-amplitude coupling (10–30 vs 200–400 Hz) | Hemibody bradykinesia + rigidity | Off | ρ = 0.49 | |
Özkurt et al. (2011) [16] | 9/18 | Ratio of spectral power ± 10 Hz around slow (200–300 Hz) and fast peaks (300–400 Hz) | Hemibody bradykinesia + rigidity | On, off | ρ = 0.36 |
Giannicola et al. (2013) [57] | 18/18 | Normalised spectral power (2–7 Hz) | Total UPDRS-III | On | R2 = 0.26 |
Wang et al. (2014) [58] | 10/15 | Spectral peak power (160–470 Hz) | Hemibody bradykinesia + rigidity | Off | R2 = 0.55 |
van Wijk et al. (2016) [18] | 33/65 | Phase-amplitude coupling (13–20 vs 150–400 Hz) | Hemibody bradykinesia + rigidity | On, off | R2 = 0.11 |
West et al. (2016) [21] | 12/24 | Absolute spectral power (5–12 Hz) | Hemibody bradykinesia + rigidity | Off | R2 = 0.33 ρ = –0.61 |
Ozturk et al. (2020) [59] | 9/9 | Normalised spectral power (4–12 Hz) | Total hemibody | Levodopa-induced changes | R2 = 0.12 |
9/9 | Normalised spectral power (4–12 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.12 | |
9/9 | Normalised phase-amplitude coupling (13–22 vs 200–300 Hz) | Total hemibody | Levodopa-induced changes | R2 = 0.11 | |
9/9 | Normalised phase-amplitude coupling (13–22 vs 200–300 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.17 | |
Weber et al. (2020) [60] | 19/38 | Differential entropy | Hemibody bradykinesiac | Off | ρ = 0.48 |
Belova et al. (2021) [61] | 22/35 | Movement-related change in 1/f spectral slope | Total UPDRS-III | Off | R2 = 0.08 |
Nie et al. (2021) [55] | 10/20 | Percentage of theta bursts with long duration | Hemibody tremor | Off | ρ = 0.46 |
Study | n Patients/Hemispheres | LFP signal feature | UPDRS items | Medication state | Outcomea |
---|---|---|---|---|---|
Beta-based | |||||
Kühn et al. (2006) [13] | 9/17 | Absolute spectral power within ± 2.5 Hz range around peak (8–35 Hz) | Hemibody tremor | Levodopa-induced changes | ρ = 0.25 p = 0.54 |
Marceglia et al. (2006) [62] | 21/21 | Absolute spectral power (13–20 Hz)b | Total UPDRS-III | Off | R2 = 0.10 p = 0.14 |
Ray et al. (2008) [51] | 5/9 | Absolute spectral peak power (8–35 Hz) | Hemibody bradykinesia + rigidity | Off | ρ = –0.35 p = 0.15 |
5/9 | Absolute spectral peak power (8–35 Hz) | Hemibody tremor | Levodopa-induced changes | ρ = –0.30 p = 0.15 | |
Kühn et al. (2009) [14] | 30/51 | Absolute spectral power within ± 5.5 Hz range around peak (8–35 Hz) | Hemibody tremor | Levodopa-induced changes | R2 = 0.00 p = 0.99 |
Chen et al. (2010) [26] | 12/23 | Lempel-Ziv complexity 13–35 Hz | Hemibody tremor | Off | ρ = –0.22 p = 0.31 |
12/23 | Absolute spectral power (13–35 Hz) | Hemibody tremor | Off | ρ = 0.48 | |
12/23 | Normalised spectral power (13–35 Hz) | Hemibody tremor | Off | ρ = 0.51 | |
Pogosyan et al. (2010) [23] | 18/36 | Phase coherence between unilateral contacts (13–35 Hz) | Hemibody tremor | Off | R2 = 0.00 |
López-Azcárate et al. (2010) [15] | 14/26 | Normalised spectral peak power (12–20 Hz) | Hemibody tremor | Off | |
Little et al. (2012) [27] | 18/36 | Coefficient of variation spectral power over time (21–33 Hz) | Hemibody tremor | Off | ρ = –0.24 p = 0.16 |
10/17 | Coefficient of variation spectral power over time (21–33 Hz) | Hemibody tremor | Levodopa-induced changes | ρ = 0.14 p = 0.60 | |
Hohlefeld et al. (2013) [52] | 10/10 | Imaginary part of coherency between unilateral contacts (10–30 Hz)b | Total UPDRS-III | Off | |
10/19 | Imaginary part of coherency between unilateral contacts (10–30 Hz)b | Total UPDRS-III | On | ||
Hohlefeld et al. (2014) [53] | 8/8 | Coherence between bilateral contacts (10–20 Hz)b | Total UPDRS-III | Off | R2 = 0.00 p = 1.00 |
8/8 | Coherence between bilateral contacts (10–20 Hz)b | Total UPDRS-III | On | ||
8/8 | Coherence between bilateral contacts (10–20 Hz)b | Total UPDRS-III | Levodopa-induced changes | ||
8/8 | Imaginary part of coherency between bilateral contacts (10–20 Hz)b | Total UPDRS-III | On | ||
8/8 | Imaginary part of coherency between bilateral contacts (10–20 Hz)b | Total UPDRS-III | Levodopa-induced changes | ||
van Wijk et al. (2016) [18] | 19/38 | Normalised spectral power (13–20 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.08 p = 0.09 |
West et al. (2016) [21] | 12/23 | Coherence between unilateral contacts (13–20 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.09 ρ = 0.40 p = 0.06 |
11/11 | Coherence between bilateral contacts (13–20 Hz)b | Bradykinesia + rigidity | Off | R2 = 0.23 ρ = 0.42 p = 0.21 | |
12/12 | Coherence between bilateral contacts (13–20 Hz)b | Bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.06 ρ = 0.13 p = 0.68 | |
12/24 | Weighted phase lag index between unilateral contacts (13–20 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.11 ρ = 0.27 p = 0.20 | |
11/11 | Weighted phase lag index between bilateral contacts (13–20 Hz)b | Bradykinesia + rigidity | Off | R2 = 0.13 ρ = 0.34 p = 0.30 | |
9/9 | Weighted phase lag index between bilateral contacts (13–20 Hz)b | Bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.08 ρ = 0.13 p = 0.74 | |
12/21 | Detrended fluctuation analysis of phase synchrony between unilateral contacts (13–20 Hz) | Hemibody bradykinesia + rigidity | Off | R2 = 0.04 ρ = 0.04 p = 0.85 | |
12/17 | Detrended fluctuation analysis of phase synchrony between unilateral contacts (13–20 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.10 ρ = –0.20 p = 0.45 | |
Beudel et al. (2017) [47] | 39/39 | Normalised spectral power (8–35 Hz)b | Total UPDRS-III | Off | ρ = 0.28 p = 0.07 |
39/78 | Normalised spectral (peak) power (8–35 Hz) | Hemibody tremor | Off | ||
Neumann et al. (2017) [20] | 12/24 | Normalised spectral power within ± 3 Hz range around peak (13–35 Hz) | Total hemibody | Levodopa-induced changes | |
Martin et al. (2018) [54] | 13/26 | Normalised spectral peak power (13–35 Hz) | Hemibody tremor | Off | ρ = –0.07 p = 0.74 |
13/26 | Absolute spectral peak power (13–35 Hz) | Total hemibody | Off | ρ = –0.14 | |
13/26 | Absolute spectral peak power (13–35 Hz) | Hemibody bradykinesia + rigidity | Off | ρ = 0.38 | |
13/26 | Absolute spectral peak power (13–35 Hz) | Hemibody tremor | Off | ρ = 0.28 | |
Ozturk et al. (2020) [59] | 9/9 | Normalised spectral power (13–22 Hz) | Total hemibody | Levodopa-induced changes | R2 = 0.06 p = 0.20 |
9/9 | Normalised spectral power (13–22 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.16 p = 0.06 | |
9/9 | Normalised spectral power (13–22 Hz) | Hemibody tremor | Levodopa-induced changes | R2 = 0.04 p = 0.75 | |
Özkurt et al. (2020) [17] | 14/26 | Nonlinearity of time series (13–30 Hz) | Hemibody bradykinesia + rigidity | Off | R2 = 0.05 p = 0.36 |
Tamir et al. (2020) [22] | 8/12 | Normalised spectral power (13–30 Hz) | Hemibody tremor | Off | R2 = 0.00 p = 0.88 |
Eisinger et al. (2020) [63] | 15/19 | Absolute spectral peak power (12–30 Hz) | Total hemibody | Off | R2 = 0.00 p = 0.83 |
15/19 | Absolute spectral peak power (12–30 Hz) | Hemibody bradykinesia + rigidityc | Off | R2 = 0.01 | |
15/19 | Absolute spectral peak power (12–30 Hz) | Hemibody tremor | Off | R2 = 0.00 p = 0.91 | |
15/19 | Amplitude of movement-related power decrease (12–30 Hz) | Total hemibody | Off | R2 = 0.08 p = 0.25 | |
15/19 | Amplitude of movement-related power decrease (12–30 Hz) | Hemibody bradykinesia + rigidityc | Off | R2 = 0.02 | |
15/19 | Amplitude of movement-related power decrease (12–30 Hz) | Hemibody tremor | Off | R2 = 0.08 p = 0.24 | |
15/19 | Beta burst duration | Hemibody bradykinesia/rigidity | Off | R2 = 0.00 | |
15/19 | Beta burst amplitude | Hemibody bradykinesia/rigidity | Off | R2 = 0.00 | |
Telkes et al. (2020) [64] | 7/8 | Normalised spectral power (13–20 Hz) | Bradykinesia/rigidity | Off | ρ = 0.66 p = 0.09 |
7/8 | Normalised spectral power (13–20 Hz) | Tremor | Off | ρ = 0.75 p = 0.11 | |
Other | |||||
Kühn et al. (2006) [13] | ?/7 | Absolute spectral power within ± 2.5 Hz range around peak (60–90 Hz) | Total hemibody | Levodopa-induced changes | ρ = –0.64 p = 0.12 |
Marceglia et al. (2006) [62] | 21/21 | Absolute spectral power (8–12 Hz)b | Total UPDRS-III | Off | R2 = 0.04 p = 0.36 |
13/13 | Absolute spectral power (60–90 Hz)b | Total UPDRS-III | On | R2 = 0.01 p = 0.64 | |
13/13 | Absolute spectral power (260–340 Hz)b | Total UPDRS-III | On | R2 = 0.10 p = 0.28 | |
Chen et al. (2010) [26] | 12/23 | Lempel-Ziv complexity 0–12 Hz | Hemibody bradykinesia + rigidity | Off | ρ = 0.07 p = 0.76 |
12/23 | Lempel-Ziv complexity 0–12 Hz | Hemibody tremor | Off | ρ = 0.07 p = 0.76 | |
López-Azcárate et al. (2010) [15] | 14/22 | Movement-related changes in phase-amplitude coupling (10–30 vs 200–400 Hz) | Hemibody bradykinesia + rigidity | Off | ρ = 0.18 p = 0.60 |
14/26 | Normalised spectral peak power (250–350 Hz) | Hemibody tremor | Off | ||
14/26 | Movement-related changes in spectral peak power (250–350 Hz) | Hemibody tremor | Off | ||
14/26 | Phase-amplitude coupling (10–30 vs 200–400 Hz) | Hemibody tremor | Off | ||
14/26 | Movement-related changes in phase-amplitude coupling (10–30 vs 200–400 Hz) | Hemibody tremor | Off | ||
Giannicola et al. (2013) [57] | 18/18 | Normalised spectral power (2–7 Hz) | Total UPDRS-III | Off | R2 = 0.13 p = 0.13 |
van Wijk et al. (2016) [18] | 33/65 | Normalised spectral power (150–400 Hz) | Hemibody bradykinesia + rigidity | On, off | R2 = 0.00 p = 0.56 |
19/38 | Normalised spectral power (150–400 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.01 p = 0.51 | |
19/38 | Phase-amplitude coupling (13–20 vs 150–400 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.10 p = 0.06 | |
West et al. (2016) [21] | 12/22 | Absolute spectral power (5–12 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.08 ρ = –0.19 p = 0.39 |
Martin et al. (2018) [54] | 13/26 | 1/f slope | Total hemibody | Off | ρ = 0.04 |
13/26 | 1/f slope | Hemibody bradykinesia + rigidity | Off | ρ = 0.02 | |
13/26 | 1/f slope | Hemibody tremor | Off | ρ = 0.08 | |
Ozturk et al. (2020) [59] | 9/9 | Normalised spectral power (4–12 Hz) | Hemibody tremor | Levodopa-induced changes | R2 = 0.05 p = 0.08 |
9/9 | Normalised spectral power (70–90 Hz) | Total hemibody | Levodopa-induced changes | R2 = 0.03 p = 0.35 | |
9/9 | Normalised spectral power (70–90 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.14 p = 0.12 | |
9/9 | Normalised spectral power (70–90 Hz) | Hemibody tremor | Levodopa-induced changes | R2 = 0.11 p = 0.17 | |
9/9 | Normalised spectral power (200–400 Hz) | Total hemibody | Levodopa-induced changes | ||
9/9 | Normalised spectral power (200–400 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | ||
9/9 | Normalised spectral power (200–400 Hz) | Hemibody tremor | Levodopa-induced changes | ||
9/9 | Ratio of normalised spectral power between slow (200–300 Hz) and fast bands (300–400 Hz) | Total hemibody | Levodopa-induced changes | R2 = 0.10 p = 0.08 | |
9/9 | Ratio of normalised spectral power between slow (200–300 Hz) and fast bands (300–400 Hz) | Hemibody bradykinesia + rigidity | Levodopa-induced changes | R2 = 0.14 p = 0.06 | |
9/9 | Ratio of normalised spectral power between slow (200–300 Hz) and fast bands (300–400 Hz) | Hemibody tremor | Levodopa-induced changes | R2 = 0.02 p = 0.37 | |
Weber et al. (2020) [60] | 19/38 | Differential entropy | Hemibody rigidity | Off | |
19/38 | Differential entropy | Hemibody tremor | Off | ||
Belova et al. (2021) [61] | 22/35 | Amplitude of movement-related power increase (30–60 Hz) | Total UPDRS-III | Off | R2 = 0.00 p = 0.60 |