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Restorative Neurology and Neuroscience 32 (2014) 411–422 DOI 10.3233/RNN-130370 IOS Press

Freezing of gait in Parkinson’s disease: Current treatments and the potential role for cognitive training Courtney C. Waltona,b , James M. Shinea , Loren Mowszowskia,b , Sharon L. Naismitha,b and Simon J.G. Lewisa,∗ a Parkinson’s b Healthy

Disease Research Clinic, Brain and Mind Research Institute, University of Sydney, NSW, Australia Brain Ageing Program, Brain and Mind Research Institute, University of Sydney, NSW, Australia

Abstract. Freezing of gait (FOG) is a complex motor symptom of Parkinson’s disease that manifests as an inability to generate effective gait, leading to a significant falls risk and a severe impact on quality of life. Research into effective treatment options has provided relatively limited benefits and is often hindered by substantial limitations. In this article, current treatment and research options are briefly discussed and a proposal for the further exploration of non-invasive therapeutic approaches is given. Recent advances in the literature continue to identify a pattern of selective executive dysfunction in patients with freezing of gait and such findings highlight a possible common underlying pathophysiology. Therefore, cognitive training is of particular interest as it may be able to improve executive processes thus reducing the manifestation of FOG. This article focuses on the existing evidence for such intervention strategies and proposes that targeted cognitive training may offer a novel treatment option for FOG that is worthy of an increased research focus. Keywords: Freezing of gait, Parkinson’s disease, cognitive training, executive function, neurorehabilitation

1. Introduction Parkinson’s disease (PD) is a progressive neurodegenerative disorder, that can manifest through a broad spectrum of both motor and non-motor features (Jankovic 2008). Freezing of gait (FOG) is a common motor symptom of PD characterised by the sudden inability to generate effective stepping and forward progression despite the intention to do so, and is often described as though one’s feet are ‘glued to the ground’ (Nutt et al., 2011). FOG is thought to occur in over half of patients in the advanced stages of PD (Giladi et al., ∗ Corresponding author: S.J.G. Lewis, Brain & Mind Research Institute, University of Sydney, 94 Mallett Street, Camperdown, New South Wales, Australia. Tel.: +61 2 9351 0702; Fax: +61 2 9351 0855; E-mail: [email protected].

2001). Furthermore, it is one of the leading causes of falls and decreased mobility (Kerr et al., 2010), significantly contributing to reduced quality of life (Moore et al., 2007). However, at present reliable and effective treatment options for FOG are limited by inconsistent results, and hindered by a poor understanding of the pathophysiological mechanisms underlying this complex symptom (Nutt et al., 2011; Shine et al., 2011; Heremans et al., 2013b). In this review, we highlight currently utilised treatment options and the areas of research thus far explored. We then conclude that while many avenues of treatment provide some relief for FOG, limitations and adverse effects suggest that further research into novel therapies is warranted. As such, we provide in-depth evidence of the cognitive aspects associated with FOG, suggesting that exploration of

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cognitive remediation as a therapeutic technique for FOG is worthy of further pursuit.

2. Pharmacological treatments for FOG in PD Medical treatment for FOG is a common avenue of treatment and research. It is well described that FOG occurs more frequently in the OFF state (Schaafsma et al., 2003) suggesting it has a dopaminergic basis. Typically, the first line of treatment for FOG is manipulation of dopaminergic treatment with the aim of keeping the patient in the ON state for longer (Nutt et al., 2011). However, L-dopa has also been known to increase FOG severity (Ambani & Van Woert 1973; Espay et al., 2012) and its effectiveness is often determined by how far the disease has progressed. While OFF state FOG frequently responds well to dopaminergic treatment such as L-dopa and selegiline in the early stages of the disease (Giladi et al., 2001; Fahn et al., 2005), it commonly becomes less responsive during the more advanced stages. It is also interesting to note that treatment using selegiline in the earlier stages of Parkinson’s disease has been associated with a lessened likelihood of developing FOG as the disease progresses, although the reason underlying this has not been identified (Shoulson 1998; Giladi et al., 2001; Shoulson et al., 2002). Methylphenidate (MPH) is another drug treatment currently increasing in research focus (Auriel et al., 2009). Commonly used in the treatment of attention disorders, this stimulant acts to inhibit pre-synaptic reuptake, particularly in the striatum leading to increased dopamine levels (Nutt et al., 2004). As detailed below, such a pharmacological response is intriguing in FOG due to the known effects of MPH on cognitive abilities that are believed to act through its specific targeting of striatal regions within prefrontal projections (Clatworthy et al., 2009). Despite promise, treatment of FOG with MPH has shown unclear findings. Positive results have been found in one group of patients with FOG but these were concurrently undergoing subthalamic nucleus (STN) stimulation (Moreau et al., 2012). Another study of patients without concurrent DBS showed a worsened Unified Parkinson’s Disease Rating Scale (UPDRS; Fahn et al., 1987) and an increase in self reported FOG (FOG-Q; Giladi et al., 2000) scores as a result of treatment compared to placebo (Espay et al., 2011). The authors of this recent randomized clinical trial concluded against the

use of MPH for gait impairment in PD. Therefore, given the relatively unknown long-term risk-to-benefit ratio of medical treatment, in addition to significant side effects observed (Leonard et al., 2004), further research will be needed before such avenues can be recommended.

3. Deep brain stimulation as a treatment for FOG in PD Where medical treatment becomes unsuccessful, some patients may undergo deep brain stimulation (DBS) in the hope of improving symptoms including FOG. However, such treatments are expensive, invasive and as with pharmacological treatment, often show mixed results. To date, the pedunculopontine nucleus (PPN) and the STN have been the most common targets of such stimulation interventions, due to their known role in gait initiation and modulation patterns (Pahapill & Lozano 2000; Hamani et al., 2004). High-frequency stimulation of the STN, which is thought to paroxysmally impair the functional output of the nucleus (Miocinovic et al., 2013), has provided some exciting initial results, with significantly large decreases in FOG severity post-surgery (Niu et al., 2012). However, numerous follow-up studies have shown that while the cardinal features of FOG may improve, the effect on FOG specifically is not maintained over time (Krack et al., 2003; Wider et al., 2008; Gervais-Bernard et al., 2009; Ricchi et al., 2012). Bilateral stimulation of the PPN has also been proposed as being efficacious for improving FOG (Mazzone et al., 2005), particularly where STN stimulation is ineffective. Such studies have been limited but have shown promising preliminary results (Stefani et al., 2007; Ferraye et al., 2010; Thevathasan et al., 2011; Thevathasan et al., 2012). Of concern, in addition to showing little improvement following surgery, some patients have become more disabled as a result of both STN and PPN DBS, especially over time, perhaps due to compensatory neural responses to the stimulation (Parsons et al., 2006; Hariz et al., 2008; van Nuenen et al., 2008; Ferraye et al., 2010). This is a vital limitation of DBS as a treatment for FOG, as any worsening of the symptom as a result of invasive surgical intervention negates the positive effects found in others. Further, patient selection is crucial in determining the suitability of such procedures, meaning many patients are not able to benefit from such treatment.

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4. Cueing and physical therapy for FOG in PD In light of the abovementioned limitations of pharmacological treatment and DBS, non-invasive techniques for the treatment of FOG must be explored to provide more options for a wider population of patients aiming for less adverse effects. One such option is cueing, which refers to the presentation of stimuli that facilitate gait initiation and/or continuation (Nieuwboer 2008). Cues can be either external (e.g., visual or auditory) or internal (e.g., cognitive prompting/instruction) and aim to provide compensatory methods for the production of efficient gait patterns. Most studies in the area focus on improving gait (e.g., step frequency, speed, stride length, etc.) rather than treating FOG episodes directly. This is theoretically sound, as improving underlying patterns that contribute to FOG is possibly more valuable. However, numerous previous trials have not specifically assessed their impact on FOG, limiting the understanding in this field. In FOG, external cueing has received the majority of attention, possibly reflecting the preserved cognitive ability presumably needed to learn and use more cognitively based techniques (Nieuwboer et al., 2007). The most consistent cue for improving gait has been the placement of horizontal lines on the floor, which are assumed to improve gait patterns via the entrainment of leg swing through the use of regular visual cues. Indeed, a number of studies have found positive immediate short-term benefits on freezing episodes as a result of parallel lines placed on the floor (Dietz et al., 1990; Griffin et al., 2011). As a result of this finding, exploration of more transferable line cues for patients has been addressed. The use of a modified walking stick which provides a slat (Dietz et al., 1990; Kompoliti et al., 2000) or a laser beam (Kompoliti et al., 2000; Bunting-Perry et al., 2013) at the base, which a patient is taught to step over to abort freezing episodes has been investigated. However, such techniques are not consistently beneficial, regardless of patients being in the ‘ON’ or ‘OFF’ dopaminergic state, and in fact have worsened performance once the stick is removed (Dietz et al., 1990), suggesting a cue-dependency effect. Auditory cueing has been shown to provide some benefit to FOG (Arias & Cudeiro 2010; Kadivar et al., 2011; Spildooren et al., 2012), by providing rhythmic cues to facilitate walking pace and initiation. The most comprehensive study of cueing to date has been the RESCUE trial (Nieuwboer et al., 2007), which

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involved nine sessions of personal at-home cueing therapy over three weeks. Importantly, outcome measures were assessed without cues in order to detect training effects. Various aspects of gait were improved, and in the FOG group, freezing was detected to have decreased significantly by 5.5% through the use of the FOG-Q. However, training-induced improvements were not sustained at a six-week follow-up, suggesting habituation to the cueing signal and perhaps highlighting the need for ongoing training to sustain benefits from training. Studies combining cueing training with physical therapy have also predominantly reported promising results. Six months of three weekly sessions with strength and balance training, combined with cueing has been shown to significantly improve FOG outcomes (Allen et al., 2010). Another study showed that observation of videos providing strategic education for FOG, combined with physical therapy over four weeks had significant improvements on FOG (Pelosin et al., 2010). Furthermore, balance and postural training over six weeks has shown significant improvements in FOG (Brichetto et al., 2006), although such benefits were short-term. Treadmill approaches have also been introduced as a way of improving gait patterns by acting as an external rhythmic pace-setter and whilst the results are preliminary, such therapy does appear to be efficacious (Herman et al., 2009). The outcomes from an extensive trial combining treadmill training with a virtual reality task proposed by Mirelman et al. (2013) may provide more significant evidence for these types of therapy. While some of the reported improvements following cueing are not always statistically significant, they may nonetheless represent clinically relevant changes. Therefore with the lack of adverse effects, future research should continue to explore this promising area (Allen et al., 2011). However, one primary limitation of such strategies is that cueing is not always appropriate for patients with significant cognitive decline as it appears to overburden cognitive resources inducing a higher risk of falls (Nieuwboer et al., 2007). This is noteworthy considering the now clear association between FOG or falls and cognitive deficits (Amboni et al., 2013; Heremans et al., 2013a) and possibly hints towards the importance of cognitive remediation in patients with FOG. Clearly, the treatments reviewed thus far have shown promising yet inconsistent results. While many studies highlight improvements, others show no improvements

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or even a worsening in symptom severity. Each treatment approach has its own limitations, and therefore while further research into all of these options is important, other avenues should also be investigated.

5. The relationship between cognition and FOG in PD Recent work has highlighted an increased interest in the link between cognitive ability and the pathophysiology of FOG. The phenomenon of freezing is not unique to gait (Giladi et al., 1992), and therefore it would appear that the underlying mechanisms of FOG operate not only through motor but also cognitive and limbic pathways (Giladi & Hausdorff 2006; Lewis & Barker 2009; Shine et al., 2013e). Furthermore, FOG episodes are often triggered by environmental stimuli that may be regarded as ‘cognitive’ in nature such as dual-tasking (Giladi et al., 2006; Rahman et al., 2008) or behaviours that require some flexible adaptation of the gait pattern, reflecting attentional demands such as passing through narrow doorways (Almeida & Lebold 2010). The relationship between falls, gait and cognition has also been established in healthy older adults (Segev-Jacubovski et al., 2011) and therefore its importance should be noted in future rehabilitation strategies where this relationship is most likely more substantial. One model of freezing suggests that the mechanism underlying FOG could reflect a reduced ability to keep different tasks (motor, cognitive &/or limbic) on-line and to successfully shift between or maintain response sets (Lewis & Barker 2009). This inability is thought to be due to the lack of neural reserve by way of depleted striatal dopamine impacting on the complementary yet competing frontostriatal pathways. According to this model, periods of motor, cognitive and/or limbic demand result in a paroxysmal episode of excessive activation of the output nuclei of the basal ganglia, triggering FOG. In support of this cognitive deficit in freezers, several studies have now found specific cognitive dysfunction to be related to FOG (Amboni et al., 2008; Amboni et al., 2010; Naismith et al., 2010b; Vandenbossche et al., 2011; Vandenbossche et al., 2012b; Shine et al., 2013f; Vandenbossche et al., 2013). Specifically, executive functions have most consistently been related to FOG. Executive functions incorporate at their core, the ability to enforce inhibitory control, the ability to show flexible thinking or ‘shift’ set, in addition to working memory

(Diamond 2013). From these functions come higher order abilities such as reasoning and problem solving, however such processes have not been linked with FOG. Amboni et al. (2008) first explored executive dysfunction associated with FOG and despite groups being otherwise well-matched, there were significant differences in cognitive ability between patients with and without FOG on executive tasks. Importantly, deficits correlated significantly and negatively with scores on the FOG-Q. Moreover, at a two-year follow-up (Amboni et al., 2010), patients with FOG demonstrated significant decline in these aspects of executive function as well as additional deficits in inhibitory control, while performance in those without FOG remained stable. In other work, higher FOGQ scores have also been shown to be significantly related to a particular and significant deficit in attentional set-shifting, as assessed through the trail-making task (TMT) (Naismith et al., 2010b). This relationship was particularly strong for ‘part B’ and ‘part B minus part A’, a score calculation that suggests a specific deficit in set-shifting after considering slowed processing speed or visuo-motor difficulty. Additional work by this group also showed that set-shifting deficits are significantly and negatively correlated with the frequency and duration of freezing episodes actually recorded during clinical assessment (Shine et al., 2013f). Vandenbossche and colleagues have also explored the link between impaired executive functioning and FOG (Vandenbossche et al., 2011; Vandenbossche et al., 2012b). They used the Attentional Network Task (ANT) in order to elucidate differences in attentional networks between freezers and non-freezers. The ANT (Fan et al., 2002) is able to calculate reaction time scores for networks concerning ‘alerting’, ‘orienting’ and ‘executive control’. The executive control network is of particular interest as it deals with conflict resolution under temporal pressure. The authors showed that performance for freezers in this task was significantly impaired compared to non-freezers even while controlling for disease duration. Taking these findings into consideration, a model by this group has been developed to describe core disturbances in automaticity and control acting as triggers for FOG (Vandenbossche et al., 2012a). In this model, FOG is thought to occur when automaticity is lost and cognitive resources become pressured. As a consequence, there may be a neural shift in activation from sub-cortical to cortical areas as a compensatory strategy. The resulting overload on cognitive resources is thought to then lead to

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a breakdown and corresponding FOG episode. This suggestion has recently been supported by further evidence of lost automaticity with patients with FOG showing a particular implicit learning deficit under increased working memory load (Vandenbossche et al., 2013). In addition to the growing body of neuropsychological evidence suggesting that executive dysfunction is associated with FOG, recent advances in neuroimaging research have provided further support to this finding. Bartels & Leenders (2008) conducted a review of such work in FOG and concluded that FOG is most likely a result of neuronal circuit dysfunction in frontal and parietal areas responsible for cognitive and attentional control. Since this review, reduced resting state functional connectivity in executive-attention (right middle frontal gyrus & angular gyrus) and visual (right occipito-temporal gyrus) neural networks has been shown to exist in freezers compared to non-freezers that significantly correlated with the clinical severity of freezing (Tessitore et al., 2012b). Furthermore, atrophy of frontal (Kostic et al., 2012) and posterior (Kostic et al., 2012; Tessitore et al., 2012a) grey matter in patients with FOG that is not evident in those without FOG or healthy controls, and that correlates with FOG severity has also been shown. There are limitations to the neuroimaging work conducted in this area due to the inability to reliably image actual gait and freezing episodes. To address this shortcoming, our group has developed a novel dual-task walking paradigm that can be used during fMRI analysis to investigate the freezing phenomenon. In this paradigm, patients are able to navigate a virtual reality environment using an alternate stepping motion with foot pedals, while undergoing scanning. Patients are presented with a series of congruent or incongruent cues which must be interpreted in order to continue or stop walking (Naismith & Lewis 2010a; Gilat et al., 2013). This VR task has demonstrated that freezing episodes are associated with significant increases in prefrontal and parietal regions (Shine et al., 2013a), which are known to mediate executive functions and have been implicated as part of a Cognitive Control Network (CCN) (Cole & Schneider 2007; Niendam et al., 2012). Additionally, a concomitant deactivation is seen in sensorimotor cortices and a number of subcortical nuclei including the bilateral caudate head, putamen and globus pallidus internus in addition to the right ventral striatum and the STN. These

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subcortical regions are known to be associated with mediating shifts between neural networks (Kimura et al., 2004). Thus, the decreased activation in such regions in addition to increased cortical activation may suggest a compensatory activation as a result of a disabled information transfer between critical neural hubs (Vandenbossche et al., 2012a; Shine et al., 2013a). Expanding on these results, it has since been shown that in FOG, there is a paroxysmal functional decoupling of activity between multiple neural networks, including the basal ganglia and CCN, and cross-talk between left and right portions of the CCN (Shine et al., 2013c). Further, a recent fMRI study looking at the phenomenon of upper-limb freezing has demonstrated that there is increased cortical activity (supplementary motor, pre-motor, prefrontal cortex and M1) in concordance with decreased activity in subcortical regions (bilateral pallidum and putamen) (Vercruysse et al., 2013). The findings of these functional imaging studies are aligned, supporting the idea of a particular dysfunctional connectivity between regions associated with cognitive control and successful motor output. To explore the role of dual-tasking on freezing, a further study compared periods of high to low cognitive load during completion of this virtual reality task (Shine et al., 2013b). Interestingly, processing cognitive information whilst performing the motor component of the paradigm was associated with increased dorsolateral prefrontal and posterior parietal cortical activity within both freezers and non-freezers. However, there was a concurrent deactivation in specific regions of the CCN, including the anterior insula, ventral striatum, pre-supplementary motor area and the sub-thalamic nuclei within freezers. Again, these results suggest that patients with FOG may be unable to recruit specific cortical and subcortical regions of the CCN effectively, known to be associated with inhibitory control, set-shifting and decision-making under temporal pressure (Ernst & Paulus 2005; Menon & Uddin 2010). The findings of these functional imaging studies in FOG help to explain the observed neuropsychological deficits, by suggesting particular functional neural abnormalities in patients with FOG that relate inefficient processing throughout frontostriatal pathways (Shine et al., 2013d). Thus the pathophysiology underlying FOG extends beyond motor dysfunction and appears to overlap strongly with an executive network dysfunction. This provides a greater appreciation of the cognitive deficits associated with FOG and a potential explanation for

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the benefits of therapeutic options such as cueing. This understanding of the neural processes also provides support for the assessment of novel therapies to be evaluated.

6. Cognitive remediation as an unexplored therapy One line of therapy yet to be explored fully in FOG is that of cognitive remediation, a non-invasive, nonpharmacological and cost-effective treatment aiming to improve cognitive function where deficits are present. The term cognitive remediation can be used generally refer to a number of techniques including cognitive stimulation, cognitive training (CT), and cognitive rehabilitation (Mowszowski et al., 2010), all of which may be of benefit in FOG. However, CT represents the most applicable and testable technique for improving executive functioning and can be delivered through computer-based activities and/or strategy-based learning. Recent work suggests that CT is a viable tool for improving cognitive function in older adults, both in health and disease, although methodological differences have clouded the interpretation of some findings (Mowszowski et al., 2010; Gates et al., 2011; Kueider et al., 2012). Despite a large body of research into cognitive intervention for other neurological disorders, research into CT for PD has been considerably limited and has not specifically evaluated the impacts on FOG (Calleo et al., 2012; Hindle et al., 2013). Generally, trials to date have suffered from numerous methodological problems, most notably a lack of adequate sample size, randomisation and blinding procedures, and control group allocation. Nevertheless, a small number of trials to investigate CT in PD thus far have reported potential benefits suggesting the need for its more rigorous exploration. 6.1. Motor-related cognitive training in non-PD patients Supporting the claim for CT in PD, there is some existing evidence that CT may prove useful for improving motor function and gait in healthy older adults. In one such study, the effects of a computerised dual-task CT program led to significant cognitive improvements that transferred to postural control in the training but not the control group (Li et al., 2010). Another study

which assigned older adults to an eight-week CT program (Mindfit) demonstrated improvements in gait speed during both normal and dual-task conditions that were not evident in control subjects (Verghese et al., 2010). Significantly, the CT program used was specifically designed to improve executive and working memory abilities. This observation suggests that improvements in executive functioning and attentional resources may be transferable to the maintenance of gait patterns. This finding supports the relationship between selected cognitive functions and gait (Yogev et al., 2005; Amboni et al., 2013) and thus promotes the worthiness of cognitive therapy as an approach for improving both of these impairments (Segev-Jacubovski et al., 2011). 6.2. Non-controlled studies of cognitive training in PD One of the early studies in PD utilised a combined motor and computerized CT program (TNP Software) which aims to stimulate specific cognitive functions such as attention, visuo-spatial ability and abstract reasoning in addition to motor rehabilitation (Sinforiani et al., 2004). This was administered over six weeks, twice weekly for one hour in twenty PD patients with early disease and improvements in verbal fluency, logical memory and logical reasoning were found. Similarly, a recent non-controlled, non-randomized study (Disbrow et al., 2012) administered computer based CT focused on number sequencing tasks in both thirty PD patients and twenty-one age-matched nonPD participants over ten days. Although caution is warranted due to the short CT duration, this study did show improvements in motor-related executive functioning in both groups after training. Interestingly, some of the most substantial improvements were seen in those PD patients who were classified as ‘impaired’ with poorer performance in TMT part ‘B minus A’. This provides some preliminary evidence that patients with FOG and executive dysfunction might be able to directly benefit from CT given the known association between freezing and this measure of trail making ability (Naismith et al., 2010b; Shine et al., 2013f). 6.3. Controlled studies of cognitive training in PD A randomized-controlled trial of CT over ten thirtyminute sessions during a four-week hospital stay

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showed improvements in tasks requiring rule-shifting in PD patients who completed the training program (N = 12) but not those who received routine treatment (N = 14) (Sammer et al., 2006). CT tasks focused on working memory and executive functioning tasks not used for outcome measures. These findings are of particular interest given that such rule shift tasks rely heavily on the CCN, which as highlighted above has been implicated in the pathophysiology underpinning FOG (Shine et al., 2013d). However, the small sample used in the study requires cautious interpretation. A blind, randomized controlled study conducted by Paris et al. (2011) compared those patients who completed both computerized and pen and pencil CT for four weeks over three-times-weekly forty-five minute sessions (N = 16) to those who completed a program of speech therapy (N = 12). Computerized training was completed on adaptive software (SmartBrain) which contained a number of differing tasks stimulating cognitive functions known to be deficient in PD. Additionally, patients completed at home a set of pen and pencil tasks designed to stimulate similar domains of cognition. As compared to the speech therapy group, the CT treatment group demonstrated improved performance in domains of attention, processing speed, memory, visuospatial skills, verbal fluency and importantly executive abilities, including TMT part B. This study further suggests that executive skills may be malleable to improvements as a result of CT in PD patients. Supporting the proposal of targeted training in PD, our own group has been able to demonstrate improvements in primary outcome measures of memory recall and delayed retention using a single-blind multifaceted educational and computerised CT program (Naismith et al., 2013). Training involved a number of computerized tasks involving both specialized CT software and computer games which trained neuropsychologists collectively deemed to stimulate appropriate cognitive functions. Training took place over seven weeks of twice weekly sessions in a sample of thirty-five PD patients in comparison to a waitlist control group. However, improvements were not seen in a number of relevant executive tasks such as the trail-making task part B-A. As this program targeted memory, it suggests that CT needs to be focused on the relevant outcome measures to be effective. Therefore, it would seem likely that a CT program focused on improving FOG must aim to improve associated aspects of executive functioning (Amboni et al., 2008; Amboni et al., 2010)

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including inhibitory control (Vandenbossche et al., 2011; Vandenbossche et al., 2012b) and set-shifting ability (Naismith et al., 2010b; Shine et al., 2013f), which represent similar cognitive domains mediated by the CCN (Cole et al., 2007; Niendam et al., 2012). 6.4. The neurological basis for CT Neuroplasticity has been suggested as being the most likely neural mechanism underlying cognitive improvement following CT (Valenzuela et al., 2007; Cramer et al., 2011). Numerous studies have now shown neuroplastic effects such as changes in structural density in grey and white matter, and altered patterns of neural activation and cerebral blood flow patterns as a result of training interventions in older adults (Engvig et al., 2010; Mozolic et al., 2010; Belleville et al., 2011; Brehmer et al., 2011; Engvig et al., 2012; Lovden et al., 2012; Kuhn et al., 2013). Additional evidence for the role of CT in PD specifically has been sought by introducing fMRI in an effort to identify the neural correlates of any cognitive improvements following intervention. In a group of ten PD patients and ten controls, a recent study demonstrated that improved performance on a stroop-like inhibitory control task following six months of Sudoku training was associated with a pattern of decreased cortical activity (Nombela et al., 2011). PD patients who completed training (N = 5) showed significantly less activation at follow-up than patients who did not complete training in a number of regions including the right putamen and left ventrolateral prefrontal cortex. The authors suggested that the CT program may have contributed to changes in the neural capacity needed to perform challenging tasks, leading to more efficient cognitive processing and thus relatively less activation patterns on fMRI, aligned with the conclusions of a recent review (Patel et al., 2013). Changes were believed to occur as a result of the high levels of attentional, working memory and inhibitory demands induced by complex Sudoku tasks (Elser et al., 2007). This study is limited by a small sample, but does importantly suggest that altered neural responses as a result of training are possible in PD. Neuroplastic changes also appear to be possible as a result of exercise in PD (Petzinger et al., 2013), and thus it appears a robust finding that the PD brain is still malleable to change. Therefore, such findings suggest that CT may facilitate either more efficient processing or altered neural mech-

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anisms in a way that could be harnessed to override inefficient gait patterns or more specifically, FOG.

7. Future directions We propose that a large scale RCT on CT in PD would be worthwhile in assessing its effects on FOG. Further, with the limited studies conducted generally, such work provides either support or a lack of, for CT in patients with PD. We propose that such a study should focus on targeted, specific training in executive functions, in particular focusing on cognitive control processes of inhibitory control and set-shifting. Sham training should be employed as an active control group in order to ensure reliability of results. Outcome measures of executive ability would then be measured as a consequence of training. If cognitive ability is improved, the final step would be to assess this in relation to objective measures of FOG. Functional imaging would be efficacious in assessing for any changes in processing tasks, such as the virtual reality task discussed previously. If such a study was to show significant changes in freezing, sustainability of effects would become important to assess, as this is a limitation of many other therapies previously outlined.

8. Conclusions With the increasingly apparent cognitive profile of specific executive deficits associated with FOG, CT provides a valid avenue for research as a therapeutic option to alleviate FOG symptoms and improve deficits in specific and related cognitive functions. CT provides no risk of harm, whereby medication and DBS may. Its implementation may be of benefit where patients suffer from impaired executive function leading to ineffective cueing therapy. Further, CT could provide additional benefits to general functioning and well-being such as improved or sustained cognition, and increased engagement in social interaction. Once implemented, CT should be focused on executive functions which have been shown to be deficient in patients who experience FOG. It is hoped that this avenue of therapy could help to strengthen deficient neural pathways or encourage the use of compensatory networks to alleviate the effects of cognitive inefficiency in FOG.

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