Nellie Georgiou-Karistianis

Gait freezing in Parkinson's disease and the stride length sequence effect interaction

Freezing of gait (FOG) has been identified as one of the main contributors to gait disturbances in Parkinsons disease. While the pathophysiology remains enigmatic, several factors such as step length and the sequence effect (step to step reduction in amplitude) may lead to the occurrence of FOG. It was hypothesized that by reducing step length, FOG episodes would present more frequently if a significant sequence effect (measured as a regression slope) was co-existent in the subject. Twenty-six participants with Parkinsons disease were separated clinically into a freezing (PD + FOG, n = 16) and non-freezing (PD-FOG, n = 10) group, with 10 age-matched control participants. Testing involved walking trials where preferred step length was set at 100%, 75%, 50% and 25% of normalized step length. The number of FOG episodes increased in the 50% condition and further increased in the 25% condition compared to other conditions. The participants with FOG also demonstrated a larger average regression slope, with significant differences in the 75%, 50% and 25% conditions when compared to the PD-FOG and control groups. There were no significant differences when comparing the slope of the PD-FOG and control group, indicating the reduced step length and the sequence effect may have led to the occurrence of FOG. These findings support the possible dual requirement of a reduced step length and a successive step to step amplitude reduction to lead to FOG.

Magnetic resonance imaging as an approach towards identifying neuropathological biomarkers for Huntington's disease

Magnetic Resonance Imaging (MRI), functional MRI (fMRI) and Diffusion Tensor Imaging (DTI) have been central to characterisation of abnormalities in brain structure and function in both clinical and preclinical Huntingtons disease (HD). One current challenge in clinical HD research is the identification of sensitive and reliable biomarkers to detect progressive neurodegeneration and neural dysfunction, which could be used to assess the effect of therapeutic intervention on brain structure and function in a HD clinical trial. To this end, both established and novel neuroimaging approaches could potentially provide sensitive, reliable and non-invasive tools to assess long-term and dynamic effects of treatment on specific brain regions, including their microstructure and connectivity. This review examines contributions from structural MRI, fMRI and DTI studies to our current understanding of preclinical and clinical HD, and critically appraises MRI methods potentially suitable for both scientific characterisation and for use as biomarkers in HD clinical trials. A combined neuroimaging approach incorporating structural MRI, fMRI and DTI is yet to be realised in HD clinical trials, however if proven to be sensitive and reliable, these methods could potentially serve as biomarkers for use in future clinical drug trials in HD.

Investigating the cortical origins of motor overflow

Motor overflow refers to the involuntary movements which may accompany the production of voluntary movements. While overflow is not usually seen in the normal population, it does present in children and the elderly, as well as those suffering certain neurological dysfunctions. Advancements in methodology over the last decade have allowed for more convincing conclusions regarding the cortical origins of motor overflow. However, despite significant research, the exact mechanism underlying the production of motor overflow is still unclear. This review presents a more comprehensive conceptualization of the theories of motor overflow, which have often been only vaguely defined. Further, the major findings are explored in an attempt to differentiate the competing theories of motor overflow production. This exploration is done in the context of a range of neurological and psychiatric disorders, in order to elucidate the possible underlying mechanisms of overflow.

Negative symptoms: A review of schizophrenia, melancholic depression and Parkinson's disease

Negative symptoms generally refer to a reduction in normal functioning. In schizophrenia they encompass apathy, anhedonia, flat affect, avolition, social withdrawal and, on some accounts, psychomotor retardation. Negative symptoms have been identified in other psychiatric disorders, including melancholic depression, and also in neurological disorders, such Parkinsons disease. Achieving a better understanding of negative symptoms constitutes a priority in mental health. Primarily, negative symptoms represent an unrelenting, intractable and disabling feature for patients, often amounting to a severe burden on families, carers and the patients themselves. Identifying and understanding subgroups within disorders may also contribute to the clinical care and scientific understanding of the pathophysiology of these disorders. The purpose of this paper is to review the current literature on negative symptoms in schizophrenia and explore the idea that negative symptoms may play an important role not only in other psychiatric disorders such as melancholic depression, but also in neurological disorders, such as Parkinsons disease. In each disorder negative symptoms manifest with similar motor and cognitive impairments and are associated with comparable neuropathological and biochemical findings, possibly reflecting analogous impairments in the functioning of frontostriatal-limbic circuits.

Functional connectivity of the prefrontal cortex in Huntington’s disease

Background: Huntington’s disease is a progressive neurodegenerative disorder that results in deterioration and atrophy of various brain regions. Aim: To assess the functional connectivity between prefrontal brain regions in patients with Huntington’s disease, compared with normal controls, using functional magnetic resonance imaging. Patients and methods: 20 patients with Huntington’s disease and 17 matched controls performed a Simon task that is known to activate lateral prefrontal and anterior cingulate cortical regions. The functional connectivity was hypothesised to be impaired in patients with Huntington’s disease between prefrontal regions of interest, selected from both hemispheres, in the anterior cingulate and dorsal lateral prefrontal cortex. Results: Controls showed a dynamic increase in interhemispheric functional connectivity during task performance, compared with the baseline state; patients with Huntington’s disease, however, showed no such increase in prefrontal connectivity. Overall, patients with Huntington’s disease showed significantly impaired functional connectivity between anterior cingulate and lateral prefrontal regions in both hemispheres compared with controls. Furthermore, poor task performance was predicted by reduced connectivity in patients with Huntington’s disease between the left anterior cingulate and prefrontal regions. Conclusions: This finding represents a loss of synchrony in activity between prefrontal regions in patients with Huntington’s disease when engaged in the task, which predicted poor task performance. Results show that functional interactions between critical prefrontal regions, necessary for cognitive performance, are compromised in Huntington’s disease. It is speculated whether significantly greater levels of activation in patients with Huntington’s disease (compared with controls) observed in several brain regions partially compensate for the otherwise compromised interactions between cortical regions.

Prefrontal activity in Huntington's disease reflects cognitive and neuropsychiatric disturbances: the IMAGE-HD study.

Functional integrity of prefrontal cortico-striatal circuits underlying executive functioning may be compromised by basal ganglia degeneration during Huntingtons disease (HD). This study investigated challenged inhibitory attentional control with a shifting response-set (SRS) task whilst assessing neural response via functional magnetic resonance imaging (fMRI) in 35 healthy controls, 35 matched pre-symptomatic (pre-HD) and 30 symptomatic (symp-HD) participants. A ≥70% performance accuracy threshold allowed confident identification of neural activity associated with SRS performance in a sub-set of 33 healthy controls, 32 pre-HD and 20 symp-HD participants. SRS activated dorsolateral prefrontal and dorsal anterior cingulate cortices, premotor, parietal, and basal ganglia regions and deactivated subgenual anterior cingulate cortex. Symp-HD participants showed greater prefrontal functional responses relative to controls and pre-HD, including larger activations and larger deactivations in response to cognitive challenge, consistent with compensatory neural recruitment. We then investigated associations between prefrontal BOLD responses, SRS performance accuracy and neuropsychiatric disturbance in all participants, including those below SRS performance accuracy threshold. We observed that reduced prefrontal responsivity in symp-HD was associated with reduced accuracy in SRS performance, and with increased neuropsychiatric disturbance within domains including executive dysfunction, pathological impulses, disinhibition, and depression. These findings demonstrate prefrontal response during inhibitory attentional control usefully characterises cognitive and neuropsychiatric status in symp-HD. The functional integrity of compensatory prefrontal responses may provide a useful marker for treatments which aim to sustain cognitive function and delay executive and neuropsychiatric disturbance.

Connectivity-based segmentation of the striatum in Huntington's disease: vulnerability of motor pathways.

The striatum, the primary site of degeneration in Huntingtons disease (HD), connects to the cerebral cortex via topographically organized circuits subserving unique motor, associative and limbic functions. Currently, it is not known whether all cortico-striatal circuits are equally affected in HD. We aimed to study the selective vulnerability of individual cortico-striatal circuits within the striatum in HD, and hypothesized that motor cortico-striatal pathways would be most affected, consistent with HD being a primarily motor disorder. Diffusion Tensor Imaging (DTI) tractography was used to identify connections between the striatum and seven major cortical regions in 12 HD patients and 14 matched controls. The striatum of both groups was parcellated into subregions based on connectivity with the cerebral cortex. Volumetric and DTI microstructural measures of Fractional Anisotropy (FA) and Mean Diffusivity (MD) were obtained within each subregion and compared statistically between groups. Tractography demonstrated the topographic organization of cortical connections in the striatum of both controls and HD patients. In HD patients, the greatest difference from controls in volume, FA and MD was observed in M1 and S1 subregions of the caudate and putamen. Motor symptoms correlated with volume and MD in sensorimotor striatal subregions, suggesting that sensorimotor striatal degeneration is closely related to motor dysfunction. DTI tractography provides a novel approach to sensitively examine circuit-specific abnormalities in HD and has identified that the motor cortico-striatal circuit is selectively vulnerable in HD.

Increased cortical recruitment in Huntington's disease using a Simon task.

Cognitive deficits in Huntingtons disease (HD) have been attributed to neuronal degeneration within the striatum; however, postmortem and structural imaging studies have revealed more widespread morphological changes. To examine the impact of HD-related changes in regions outside the striatum, we used functional magnetic resonance imaging (fMRI) in HD to examine brain activation patterns using a Simon task that required a button press response to either congruent or incongruent arrow stimuli. Twenty mild to moderate stage HD patients and 17 healthy controls were scanned using a 3T GE scanner. Data analysis involved the use of statistical parametric mapping software with a random effects analysis model to investigate group differences brain activation patterns compared to baseline. HD patients recruited frontal and parietal cortical regions to perform the task, and also showed significantly greater activation, compared to controls, in the caudal anterior cingulate, insula, inferior parietal lobules, superior temporal gyrus bilaterally, right inferior frontal gyrus, right precuneus/superior parietal lobule, left precentral gyrus, and left dorsal premotor cortex. The significantly increased activation in anterior cingulate-frontal-motor-parietal cortex in HD may represent a primary dysfunction due to direct cell loss or damage in cortical regions, and/or a secondary compensatory mechanism of increased cortical recruitment due to primary striatal deficits.

Diffusion Tensor Imaging in Huntington’s disease reveals distinct patterns of white matter degeneration associated with motor and cognitive deficits

White matter (WM) degeneration is an important feature of Huntington’s disease (HD) neuropathology. To investigate WM degeneration we used Diffusion Tensor Imaging and Tract-Based Spatial Statistics to compare Fractional Anisotropy, Mean Diffusivity (MD), parallel diffusivity and perpendicular diffusivity (λ⊥) in WM throughout the whole brain in 17 clinically diagnosed HD patients and 16 matched controls. Significant WM diffusivity abnormalities were identified primarily in the corpus callosum (CC) and external/extreme capsules in HD patients compared to controls. Significant correlations were observed between motor symptoms and MD in the CC body, and between global cognitive impairment and λ⊥ in the CC genu. Probabilistic tractography from these regions revealed degeneration of functionally relevant interhemispheric WM tracts. Our findings suggest that WM degeneration within interhemispheric pathways plays an important role in the deterioration of cognitive and motor function in HD patients, and that improved understanding of WM pathology early in the disease is required.

A longitudinal diffusion tensor imaging study in symptomatic Huntington's disease

Objective The striatum and its projections are thought to be the earliest sites of Huntingtons disease (HD) pathology. This study aimed to investigate progression of striatal pathology in symptomatic HD using diffusion tensor imaging. Method Diffusion weighted images were acquired in 18 HD patients and in 17 healthy controls twice, 1 year apart. Mean diffusivity (MD) was calculated in the caudate, putamen, thalamus and corpus callosum, and compared between groups. In addition, caudate width was measured using T1 high resolution images and correlated with caudate MD. Correlation analyses were also performed in HD between caudate/putamen MD and clinical measures. Results MD was significantly higher in the caudate and putamen bilaterally for patients compared with controls at both time points although there were no significant MD differences in the thalamus or corpus callosum. For both groups, MD did not change significantly in any region from baseline to year 1. There was a significant negative correlation between caudate width and MD in patients at baseline but no correlation between these parameters in controls. There was also a significant negative correlation between Mini-Mental State Examination scores and caudate MD and putamen MD at both time points in HD. Conclusions It appears that microstructural changes influence cognitive status in HD. Although MD was significantly higher in HD compared with controls at both time points, there were no longitudinal changes in either group. This finding does not rule out the possibility that MD could be a sensitive biomarker for detecting early change in preclinical HD.