Fig. 8.1
Visual hemineglect in copying Rey figure. The patient largely ignores the left side of the figure and copies only parts of the right side
Finally, neglect is an independent predictor of poor rehabilitation outcome, in terms of more limited functional independence (Stone et al. 1992; Di Monaco et al. 2011) and lower likelihood of being discharged home (Wee and Hopman 2005, 2008).
Depending on the applied assessment tools, the reported incidence of neglect widely varies between 10 and 82 % following right-hemispheric lesions and between 15 and 65 % following left-hemispheric lesions (for a review, see Plummer et al. 2003).
Noninvasive brain stimulation, such as repetitive transcranial magnetic stimulation (rTMS), is one of the different therapeutic strategies to treat neglect that have been evaluated so far. Visual scanning training, prism adaptation, neck muscle vibration, sensory stimulation, and optokinetic stimulation have also been tested (for a review, see Bowen et al. 2002; Kerkhoff and Schenk 2012). These approaches have been shown to reduce the severity of neglect. However, they are often difficult to use in a rehabilitation setting – particularly during the acute or subacute phase of stroke – due to the short duration of their effects, patient discomfort, or the difficulty for patients to cooperate, as mentioned by Fierro and colleagues (2006).
8.2 The Concept of Interhemispheric Rivalry in Hemineglect
The interhemispheric rivalry concept by Kinsbourne (1987, 1993) is so far very influential for the application of rTMS in neglect. According to this concept, the parietal cortices compete to direct attention toward the contralateral space, thereby exerting a reciprocal interhemispheric inhibition. A damage to the right parietal cortex causes a disinhibition of the intact, left parietal cortex and thus a hyperactivation of the latter. This hyperactivation triggers an increased inhibition on the damaged hemisphere, further depressing the neural activity in the latter. These dynamics result in a rightward, ipsilesional attentional bias. Evidence supporting this concept comes from several sources, including animal studies, correlational fMRI studies in humans, and interventional TMS studies. Several animal studies (e.g., Sprague 1966; Payne and Rushmore 2004; Rushmore et al. 2006; Valero-Cabré et al. 2006) showed that unilateral inhibitory interventions introduce an imbalance in the physiological activity between the networks controlling visuospatial attention in the two hemispheres, favoring the intact hemisphere and leading to visual neglect. The reduction of this imbalance (and, as a consequence, of the visual neglect) is possible through the reduction of the hyperexcitability of specific cortical or subcortical regions in the intact hemisphere, by a lesion or cooling.
In humans, functional magnetic resonance imaging (fMRI) studies showed a relative hyperactivity of the left, undamaged hemisphere in neglect patients, which correlated with the severity of the disorder (Corbetta et al. 2005). The recovery of neglect correlated with the restoration and rebalancing of the activity between the damaged and the undamaged hemisphere, particularly in the dorsal parietal cortices (Corbetta et al. 2005; He et al. 2007). Finally, Koch and colleagues (2011, 2012) demonstrated a pathological hyperexcitability of the intact, contralesional area in neglect patients by means of a twin-coil TMS technique. They assessed the excitability within parieto-motor cortical circuits and showed a significantly higher left-hemispheric excitability in neglect patients as compared to healthy controls or to patients with right-hemispheric lesions but no neglect. This hyperexcitability was also significantly correlated with neglect severity. The application of inhibitory rTMS over the left, contralesional posterior parietal cortex significantly reduced the hyperexcitability of this area, as measured by motor evoked potentials (MEP), and resulted in a significant reduction of neglect severity.
8.3 Methods
The following databases were searched for studies published in English: PubMed, PsycINFO, and ScienceDirect. The following search terms were used: neglect, visual neglect, unilateral neglect, rehabilitation, and TMS. Furthermore, previous reviews concerning treatment of hemineglect by rTMS were consulted (Cazzoli et al. 2010; Hesse et al. 2011; Müri et al. 2013; Schulz et al. 2013; Yang et al. 2013). Studies were included in the review if they satisfied the following criteria: use of an offline TMS protocol, treatment of hemineglect, or evaluation of the duration of TMS effects on hemineglect, as a goal of the study.
8.4 Calculation of TMS Treatment Effect Sizes and Levels of Evidence
Since treatment effects between an intervention and a control group were rarely reported in the studies, we calculated the relative magnitude according to the data presented in the publications. For data collected with repeated measures designs (Brighina et al. 2003; Cazzoli et al. 2012; Koch et al. 2011; Kim et al. 2010; Nyffeler et al. 2009; Song et al. 2009), we used the F-ratios and the degrees of freedom provided in the respective publications (degrees of freedom were either provided or had to be calculated) in order to calculate the effect size measure r by applying Andy Field’s formula (2009). For independent-group pretest–posttest designs, where statistical data was presented in gain scores (Kim et al. 2013; Lim et al. 2010), the effect size measure d was computed using Morris and DeShon’s method (2002). Finally, for the purpose of comparison, these effect sizes were rated according to the guidelines for r and d, respectively (Field 2009).
The level of evidence of the studies was evaluated according to the guidelines of the OCEBM Levels of Evidence (http://www.cebm.net/ocebm-levels-of-evidence/).
8.5 Results
We found ten studies that used rTMS for visual hemineglect treatment. A total of 133 patients were involved. The number of patients included in the studies varied considerably, from a single case report (Bonni et al. 2013) to 27 patients (Kim et al. 2013). The overview of the studies is presented in Table 8.1.
Table 8.1
Characteristics of the studies
Author | Year | No. of patients (no. of males) | Etiology | Mean age (SD) | Mean time post (SD) | Additional rehabilitation therapy | Sham/control (no.) | Stimulation site | Coil used | No. of pulses per session frequency intensity | No. of stimulation sessions |
|---|---|---|---|---|---|---|---|---|---|---|---|
Brighina et al. | 3 (3) | Ischemia | 52 (5.5) | 4 months (1.2) | No | No/(5) | Contra (P5) | Figure 8 | 900 1 Hz 90 % MT | One session, every 2nd day | |
Shindo et al. | 2 (1) | Ischemia | 60 (1) | 175 days, 186 days | Yes | No | Contra (P5) | Figure 8 | 900 0.9 Hz 95 % MT | One session, three times per week | |
Nyffeler et al. | 11 (na) | Ischemia/hemorrhage | 54 (8.7) | 7 months (13.0) | Yes | Yes/(5) | Contra (P3) | Round coil | 801 TBS 30 Hz 100 % MT | Two sessions per day Four sessions per day | |
Song et al. | 14 (8) | Ischemia/hemorrhage | 56 (9.0) 64 (12.6) | 38 days (15.2) 32 days (11.5) | Yes | Yes/(7) | Contra (P3) | Figure 8 | 450 0.5 Hz 90 % MT | Two sessions per day | |
Kim et al. | 19 (10) | Ischemia | 62 (11.2) | 24 months (12.3) | Na | Yes | Contra (P3), ipsi (P4) | Figure 8 | 1200 1 Hz contra/20 Hz ipsi 90 % MT | One session | |
Lim et al. | 14 (4) | Ischemia/hemorrhage | 72 (5.3) 66 (15.2) | 62 days (111.1) 139 days (194.8) | Yes | No/(7) | Contra (P5) | Figure 8 | 900 1 Hz 90 % MT | One session, five times per week | |
Cazzoli et al. | 24 (17) | Ischemia/hemorrhage | 58 (2.3) | 27 days (4.4) | Yes | Yes/(8) | Contra (P3) | Round coil | 801 TBS 30 Hz 100 % MT | Two sessions per day | |
Koch et al. | 18 (10) | Ischemia | 61 (13.0) 72 (4.9) | 50 days (29.4) 37 days (10.5) | Yes | Yes | Contra (P3) neuronavigation | Figure 8 | 600 TBS 50 Hz 80 % MT | One session, five times per week | |
Kim et al. | 27 (15) | Ischemia | 69 (14.4) 64 (10.3) 68 (6.5) | 14 days (4.7) 14 days (3.6) 16 days (8.5) | Yes | Yes | Contra (P3), ipsi (P4) | Figure 8 | 1200 1 Hz 90 % MT 1000 20 Hz 90 % MT | One session, five times per week | |
Bonni et al. | 1 (1) | Brain trauma | 20 | 24 months | No | No | Contra (P3) | Figure 8 | 600 TBS 50 Hz 80 % MT | Two sessions per day |
8.5.1 rTMS Protocols
All studies used inhibitory protocols, such as low-frequency rTMS (i.e., 1 Hz or below) or continuous theta burst stimulation (cTBS; with 50 or 30 Hz bursts). Five studies used low-frequency rTMS (Brighina et al. 2003; Shindo et al. 2006; Koch et al. 2011; Song et al. 2009; Lim et al. 2010), with frequencies of 0.5, 0.9, or 1 Hz, applied over the contralesional hemisphere. Seventy-nine patients took part in these studies. Furthermore, Kim and colleagues (2010; 2013) compared the effects of low-frequency rTMS over the contralesional hemisphere with those of high-frequency rTMS (20 Hz) over the ipsilesional hemisphere. Four studies, which included 35 patients in total, used cTBS (Nyffeler et al. 2009; Cazzoli et al. 2012; Koch et al. 2012; Bonni et al. 2013) over the contralesional hemisphere. The number of rTMS pulses varied between 450 (Song et al. 2009) and 1200 pulses (Kim et al. 2010; 2013) per session; the cumulative number varied between 1602 (Nyffeler et al. 2009) and 12,600 pulses (Song et al. 2009). The intervention duration varied between a single session (Kim et al. 2010) and 28 sessions (Song et al. 2009; Bonni et al. 2013). With the exception of two studies that used a round coil (Nyffeler et al. 2009; Cazzoli et al. 2012), all other studies used a focal, figure-of-eight coil. Nine studies explicitly reported that there was no harm or side effects of rTMS application. In one study (Kim et al. 2001), side effects were not mentioned.
8.5.2 Localization of Target Region
Nine studies located the target stimulation site using the international 10–20 EEG system. In seven studies, P3 was targeted. Two studies targeted in addition P4 for high-frequency, excitatory stimulation (Kim et al. 2010, 2013). Two other studies stimulated over P5 (Brighina et al. 2003; Shindo et al. 2006). Only one study used a neuronavigation system (Koch et al. 2012). In this study, the left PPC was targeted, positioning the coil over the angular gyrus, close to the posterior part of the adjoining intraparietal sulcus, based on individual anatomic MRI scans.
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