Anomalies in global network connectivity associated with early recovery from alcohol dependence: A network transcranial magnetic stimulation and electroencephalography study.

Although previous research in alcohol dependent populations identified alterations within local structures of the addiction 'reward' circuitry, there is limited research into global features of this network, especially in early recovery. Transcranial magnetic stimulation (TMS) is capable of non-invasively perturbing the brain network while electroencephalography (EEG) measures the network response. The current study is the first to apply a TMS inhibitory paradigm while utilising network science (graph theory) to quantify network anomalies associated with alcohol dependence. Eleven individuals with alcohol-dependence (ALD) in early recovery and 16 healthy controls (HC) were administered 75 single pulses and 75 paired-pulses (inhibitory paradigm) to both the left and right prefrontal cortex (PFC). For each participant, Pearson cross-correlation was applied to the EEG data and correlation matrices constructed. Global network measures (mean degree, clustering coefficient, local efficiency and global efficiency) were extracted for comparison between groups. Following administration of the inhibitory paired-pulse TMS to the left PFC, the ALD group exhibited altered mean degree, clustering coefficient, local efficiency and global efficiency compared to HC. Decreases in local efficiency increased the prediction of being in the ALD group, while all network metrics (following paired-pulse left TMS) were able to adequately discriminate between the groups. In the ALD group, reduced mean degree and global clustering was associated with increased severity of past alcohol use. Our study provides preliminary evidence of altered network topology in patients with alcohol dependence in early recovery. Network anomalies were predictive of high alcohol use and correlated with clinical features of alcohol dependence. Further research using this novel brain mapping technique may identify useful network biomarkers of alcohol dependence and recovery.

Measuring Inhibition and Cognitive Flexibility in Friedreich Ataxia.

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with subtle impact on cognition. Inhibitory processes and cognitive flexibility were examined in FRDA by assessing the ability to suppress a predictable verbal response. We administered the Hayling Sentence Completion Test (HSCT), the Trail Making Test, and the Stroop Test to 43 individuals with FRDA and 42 gender- and age-matched control participants. There were no significant group differences in performance on the Stroop or Trail Making Test whereas significant impairment in cognitive flexibility including the ability to predict and inhibit a pre-potent response as measured in the HSCT was evident in individuals with FRDA. These deficits did not correlate with clinical characteristics of FRDA (age of disease onset, disease duration, number of guanine-adenine-adenine repeats on the shorter or larger FXN allele, or Friedreich Ataxia Rating Scale score), suggesting that such impairment may not be related to the disease process in a straightforward way. The observed specific impairment of inhibition and predictive capacity in individuals with FRDA on the HSCT task, in the absence of impairment in associated executive functions, supports cerebellar dysfunction in conjunction with disturbance to cortico-thalamo-cerebellar connectivity, perhaps via inability to access frontal areas necessary for successful task completion.

Neuromodulation of Attentional Control in Major Depression: A Pilot DeepTMS Study.

While Major Depressive Disorder (MDD) is primarily characterized by mood disturbances, impaired attentional control is increasingly identified as a critical feature of depression. Deep transcranial magnetic stimulation (deepTMS), a noninvasive neuromodulatory technique, can modulate neural activity and induce neuroplasticity changes in brain regions recruited by attentional processes. This study examined whether acute and long-term high-frequency repetitive deepTMS to the dorsolateral prefrontal cortex (DLPFC) can attenuate attentional deficits associated with MDD. Twenty-one MDD patients and 26 matched control subjects (CS) were administered the Beck Depression Inventory and the Sustained Attention to Response Task (SART) at baseline. MDD patients were readministered the SART and depressive assessments following a single session (n = 21) and after 4 weeks (n = 13) of high-frequency (20 Hz) repetitive deepTMS applied to the DLPFC. To control for the practice effect, CS (n = 26) were readministered the SART a further two times. The MDD group exhibited deficits in sustained attention and cognitive inhibition. Both acute and long-term high-frequency repetitive frontal deepTMS ameliorated sustained attention deficits in the MDD group. Improvement after acute deepTMS was related to attentional recovery after long-term deepTMS. Longer-term improvement in sustained attention was not related to antidepressant effects of deepTMS treatment.

Self-Regulation of Driving Behavior in People with Parkinson Disease.

OBJECTIVE: To determine the extent and nature of driving self-regulation in drivers with Parkinson disease (PD) and factors associated with self-regulatory practices. BACKGROUND: Although people with PD have consistently been shown to have driving impairments, few studies have examined self-regulatory driving practices and their relationship to driving performance. METHODS: We used a self-report driving questionnaire to examine driving self-regulation in 37 drivers with PD and 37 healthy age-matched controls. We also analyzed factors associated with self-regulatory practices, primarily demographic, disease-related, psychological, and simulated driving performance variables. RESULTS: The drivers with PD reported significantly higher rates of self-perceived decline in their driving ability (P=0.008) and driving significantly shorter distances per week (P=0.004) than controls. Unfamiliar situations (P=0.009), in-car distractions (P<0.001), low visibility conditions (P=0.004), and long journeys (P=0.003) were particularly challenging for the drivers with PD, and their pattern of driving avoidance mirrored these difficulties. The use of self-regulatory strategies among drivers with PD was associated with female sex (rho=0.42, P=0.009) and perceived decline in driving ability (rho=-0.55, P<0.001), but not with age or objective measures of disease severity, cognition, or simulated driving performance. CONCLUSIONS: Drivers with PD reported driving less overall and restricting their driving to avoid particularly difficult circumstances. Further research is warranted on effective use of self-regulation strategies to improve driving performance in people with PD.

Symptoms of PTSD Associated With Painful and Nonpainful Vicarious Reactivity Following Amputation.

Although the experience of vicarious sensations when observing another in pain have been described postamputation, the underlying mechanisms are unknown. We investigated whether vicarious sensations are related to posttraumatic stress disorder (PTSD) symptoms and chronic pain. In Study 1, 236 amputees completed questionnaires about phantom limb phenomena and vicarious sensations to both innocuous and painful sensory experiences of others. There was a 10.2% incidence of vicarious sensations, which was significantly more prevalent in amputees reporting PTSD-like experiences, particularly increased arousal and reexperiencing the event that led to amputation (φ = .16). In Study 2, 63 amputees completed the Empathy for Pain Scale and PTSD Checklist-Civilian Version. Cluster analyses revealed 3 groups: 1 group did not experience vicarious pain or PTSD symptoms, and 2 groups were vicarious pain responders, but only 1 had increased PTSD symptoms. Only the latter group showed increased chronic pain severity compared with the nonresponder group (p = .025) with a moderate effect size (r = .35). The findings from both studies implicated an overlap, but also divergence, between PTSD symptoms and vicarious pain reactivity postamputation. Maladaptive mechanisms implicated in severe chronic pain and physical reactivity posttrauma may increase the incidence of vicarious reactivity to the pain of others.

Cognitive deficits in Friedreich ataxia correlate with micro-structural changes in dentatorubral tract.

Atrophy of the dentate nucleus is one of the major neuropathological changes in Friedreich ataxia (FRDA). Neuroimaging studies demonstrated white matter (WM) degeneration in FRDA. In this study, we used advanced tractography techniques to quantitatively measure WM changes in the dentato-thalamic and dentato-rubral tracts, and correlated these changes with cognitive profiles of FRDA. We also analysed diffusivity changes of the thalamo-cortical tract to assess whether neurological degeneration of WM extends beyond the primary site of involvement in FRDA. Twelve genetically proven individuals with FRDA and 14 controls were recruited. Sixty directions diffusion tensor images were acquired. The WM bundles from the dentate nucleus were estimated using a constrained spherical deconvolution method and the diffusivity characteristics measured. The Simon task was used to assess cognitive profile of FRDA. The dentato-rubral, dentato-thalamic and thalamo-cortical tracts manifested significantly lower fractional anisotropy, higher mean diffusivity and increased radial diffusivity in FRDA compared with controls. There was no difference in axial diffusivity between the two groups. The mean and radial diffusivity of the dentato-rubral tract was positively correlated with choice reaction time, congruent reaction time, incongruent reaction time and Simon effect reaction time and negatively with the larger GAA repeat. Significant changes in diffusivity characteristics were observed in the dentato-thalamic and thalamo-cortical tracts, suggesting extensive WM degeneration and affected WM structures in FRDA. Correlation of WM changes in the dentato-rubral tract with the cognitive assessment suggested that this tract is an important contributor to cognitive disturbances in FRDA.

Exploring inhibitory deficits in female premutation carriers of fragile X syndrome: through eye movements.

There is evidence which demonstrates that a subset of males with a premutation CGG repeat expansion (between 55 and 200 repeats) of the fragile X mental retardation 1 gene exhibit subtle deficits of executive function that progressively deteriorate with increasing age and CGG repeat length. However, it remains unclear whether similar deficits, which may indicate the onset of more severe degeneration, are evident in female PM-carriers. In the present study we explore whether female PM-carriers exhibit deficits of executive function which parallel those of male PM-carriers. Fourteen female fragile X premutation carriers without fragile X-associated tremor/ataxia syndrome and fourteen age, sex, and IQ matched controls underwent ocular motor and neuropsychological tests of select executive processes, specifically of response inhibition and working memory. Group comparisons revealed poorer inhibitory control for female premutation carriers on ocular motor tasks, in addition to demonstrating some difficulties in behaviour self-regulation, when compared to controls. A negative correlation between CGG repeat length and antisaccade error rates for premutation carriers was also found. Our preliminary findings indicate that impaired inhibitory control may represent a phenotype characteristic which may be a sensitive risk biomarker within this female fragile X premutation population.

Movement planning and online control in multiple sclerosis: assessment using a Fitts law reciprocal aiming task.

OBJECTIVE: We sought to quantify subtle changes in motor control in multiple sclerosis (MS) using a Fitts law reciprocal aiming task presented on a computer touchscreen. BACKGROUND: Upper-limb motor control is impaired in MS. However, many commonly used motor assessments do not detect subtle changes in motor function or differentiate between aspects of movement such as planning and online control. Fitts law states that movement time varies as a function of task difficulty, with smaller targets and greater distances making the task more difficult. METHODS: We gave a Fitts aiming task to 22 patients with MS and 22 matched controls. We manipulated movement difficulty by changing the targets' size and distance apart. RESULTS: The patients spent a significantly longer time than the controls stationary in each target before starting the next movement, and had a lower peak velocity, suggesting deficits in movement planning. The patients also spent longer in the deceleration phase of each movement, indicating deficits in the online control of movement. CONCLUSIONS: The computerized Fitts task allows quick, easy, and sensitive measurement of subtle aspects of movement. This task should be useful in clinical and research settings for assessing MS motor symptoms, disease progression, and treatment efficacy.

Impaired response inhibition is associated with self-reported symptoms of depression, anxiety, and ADHD in female FMR1 premutation carriers.

Fragile X Mental Retardation 1 (FMR1) premutation carriers (PM-carriers) have a defective trinucleotide expansion on the FMR1 gene that is associated with continuum of neuropsychological and mental disorders. Currently, little is known about the distinct subcomponents of executive function potentially impaired in female PM-carriers, and there have been no investigations into associations between executive function and incidences of mental disorders. A total of 35 female PM-carriers confirmed by Asuragen triple primed PCR DNA testing and 35 age- and intelligence-matched controls completed tests of executive function (i.e., response inhibition and working memory) and self-reported on social anxiety, depression, and ADHD predominantly inattentive (ADHD-PI) symptoms. Compared to controls, PM-carriers were significantly elevated on self-reported social anxiety and ADHD-PI symptoms. Irrespective of mental symptoms, female PM-carries performed significantly worse than controls on a response inhibition test, and further investigations revealed significant correlations between executive function performance and self-reported symptoms of anxiety, depression and ADHD-PI. Critically, among PM-carriers with good executive function performance, no women exceeded threshold markers for probable caseness of mental disorder. However, rates of probable caseness were elevated in those with average performance (response inhibition: social anxiety: 41.7%; depression: 20%; ADHD: 44.4%; working memory: social anxiety: 27.3%; depression: 9.1%; ADHD: 18.2%) and highly elevated for those with poor executive function performance (response inhibition: social anxiety: 58.3%; depression: 80%; ADHD: 55.6%; working memory: social anxiety: 100%; depression: 50%; ADHD: 83.3%). These data suggest that subtle executive dysfunction may be a useful neuropsychological indicator for a range of mental disorders previously reported in female PM-carriers.

Characterizing the developmental profile of effort-induced motor overflow across a timed trial.

Motor overflow is overt involuntary movement that accompanies voluntary movement. This study investigated the change in overflow production across a timed trial and the factors that affected this profile. Seventeen children (aged 8-11 years), 17 young adults (aged 18-35 years), and 17 older adults (aged 60-80 years) performed a 5-s finger pressing task by exerting 33% or 66% of their maximal force output using either index finger. Overflow was recorded as force from the alternative index finger. Young adult overflow remained stable over the 5 s. The rate of overflow increase over time was significantly greater for children than young adults. There was also a tendency for a greater overflow increase in older adults than in young adults. This overflow gradient was also greater in the right hand, particularly for children. These findings indicate that the neurological processes underlying overflow production are age dependent. Overflow progressed in a dynamic fashion over the course of a trial in children and older adults, probably because of increased bilateral cortical activation and the facilitation of motor task performance. This study is unique in quantitatively capturing the dynamic profile of overflow production in healthy participants across the life span.

Enhanced corticospinal response to observed pain in pain synesthetes.

Observing noxious injury to another's hand is known to induce corticospinal inhibition that can be measured in the observer's corresponding muscle. Here, we investigated whether acquired pain synesthetes, individuals who experience actual pain when observing injury to another, demonstrate less corticospinal inhibition than do controls during pain observation, as a potential mechanism for the experience of vicarious pain. We recorded motor-evoked potentials (MEPs) induced at two time points through transcranial magnetic stimulation while participants observed videos of a hand at rest, a hypodermic needle penetrating the skin, a Q-tip touching the skin, and a hypodermic needle penetrating an apple. We compared MEPs in three groups: 7 amputees who experience pain synesthesia, 11 nonsynesthete amputees who experience phantom limb pain, and 10 healthy controls. Results indicated that the pain synesthete group demonstrated significantly enhanced MEP response to the needle penetrating the hand, relative to the needle not having yet penetrated the hand, as compared with controls. This effect was not observed exclusively in the same muscle where noxious stimulation was applied. We speculate that our findings reflect a generalized response to pain observation arising from hyperactivity of motor mirror neurons not involved in direct one-to-one simulation but, rather, in the representation of another's experience.

Stop task after-effects in schizophrenia: behavioral control adjustments and repetition priming.

Stop task after-effects are behavioral consequences of response inhibition (i.e., slowed response time), and may index both behavioral control adjustments and repetition priming. Patients with schizophrenia and healthy controls completed a stop task, and responses to the go signal were analyzed according to characteristics of the immediately preceding trial. Schizophrenia was associated with reduced slowing following unsuccessful response inhibition, however there was no evidence of impairments in repetition priming. These results support neurocognitive models of schizophrenia that suggest an absence or reduction of behavioral adjustments (perhaps reflecting impaired error detection), but are inconsistent with current retrieval-based repetition priming accounts.

Deficits in selective attention in symptomatic Huntington disease: assessment using an attentional blink paradigm.

BACKGROUND: Impaired selective attention in Huntington disease (HD) may manifest as difficulty in identifying a single target embedded among a series of distractors in rapid serial visual presentation tasks. METHOD: We used an attentional blink (AB) paradigm to examine whether attentional control is impaired in symptomatic HD. Fourteen HD patients and 13 age-matched healthy controls performed a rapid serial visual presentation task in which 2 targets (T1 and T2) and numerous distractors were presented in rapid succession. We assessed the accuracy of T1 identification and the AB (impaired T2 detection after the correct identification of T1). RESULTS: Among the HD patients, identification of T1 was significantly impaired and AB was significantly larger but not longer. The HD patients also made significantly more random errors. CONCLUSIONS: Frontostriatal or frontoparietal dysfunction is likely to compromise attentional control in HD, such that well-masked and rapidly presented target stimuli are difficult to detect and identify, especially as the difficulty level increases. Although we previously reported no AB deficits in presymptomatic HD, with manifest disease we found that the progressive frontoparietal cortical changes compromise attentional control mechanisms.

Paralyzed by desire: a new type of body integrity identity disorder.

BACKGROUND: Body incongruity in body integrity identity disorder (BIID) manifests in the desire to have a healthy limb amputated. We describe a variant of the disorder: the desire to become paralyzed (paralysis-BIID). METHOD: Sixteen otherwise healthy participants, recruited through Internet-based forums, websites, or word of mouth, completed questionnaires about details of their desire and accompanying symptoms. RESULTS: Onset of the desire for paralysis typically preceded puberty. All participants indicated a specific level for desired spinal cord injury. All participants simulated paralysis through mental imagery or physical pretending, and 9 (56%) reported erotic interest in paraplegia and/or disability. Our key new finding was that 37.5% of paralysis-BIID participants were women, compared with 4.4% women in a sample of 68 individuals with amputation-BIID. CONCLUSIONS: BIID reflects a disunity between self and body, usually with a prominent sexual component. Sex-related differences are emerging: unlike men, a higher proportion of women desire paralysis than desire amputation, and, while men typically seek unilateral amputation, women typically seek bilateral amputation. We propose that these sex-related differences in BIID manifestation may relate to sex differences in cerebral lateralization, or to disruption of representation and/or processing of body-related information in right-hemisphere frontoparietal networks.

Characterising the neuropathology and neurobehavioural phenotype in Friedreich ataxia: a systematic review.

Friedreich ataxia (FRDA), the most common of the hereditary ataxias, is an autosomal recessive, multisystem disorder characterised by progressive ataxia, sensory symptoms, weakness, scoliosis and cardiomyopathy. FRDA is caused by a GAA expansion in intron one of the FXN gene, leading to reduced levels of the encoded protein frataxin, which is thought to regulate cellular iron homeostasis. The cerebellar and spinocerebellar dysfunction seen in FRDA has known effects on motor function; however until recently slowed information processing has been the main feature consistently reported by the limited studies addressing cognitive function in FRDA. This chapter will systematically review the current literature regarding the neuropathological and neurobehavioural phenotype associated with FRDA. It will evaluate more recent evidence adopting systematic experimental methodologies that postulate that the neurobehavioural phenotype associated with FRDA is likely to involve impairment in cerebello-cortico connectivity.

Body integrity identity disorder: deranged body processing, right fronto-parietal dysfunction, and phenomenological experience of body incongruity.

Body integrity identity disorder (BIID) is characterised by profound experience of incongruity between the biological and desired body structure. The condition manifests in "non-belonging" of body parts, and the subsequent desire to amputate, paralyse or disable a limb. Little is known about BIID; however, a neuropsychological model implicating right fronto-parietal and insular networks is emerging, with potential disruption to body representation. We argue that, as there is scant systematic research on BIID published to date and much of the research is methodologically weak, it is premature to assume that the only process underlying bodily experience that is compromised is body representation. The present review systematically investigates which aspects of neurological processing of the body, and sense of self, may be compromised in BIID. We argue that the disorder most likely reflects dysregulation in multiple levels of body processing. That is, the disunity between self and the body could arguably come about through congenital and/or developmental disruption of body representations, which, together with altered multisensory integration, may preclude the experience of self-attribution and embodiment of affected body parts. Ulimately, there is a need for official diagnostic criteria to facilitate epidemiological characterisation of BIID, and for further research to systematically investigate which aspects of body representation and processing are truly compromised in the disorder.

Utilisation of advance motor information is impaired in Friedreich ataxia.

Friedreich ataxia (FRDA) is the most common of the genetically inherited ataxias. We sought to examine motor planning ability in 13 individuals with FRDA and 13 age- and sex-matched control participants using two experimental paradigms that examined the ability to incorporate different levels of advance information to plan sequential movements. Individuals with FRDA demonstrated a differential pattern of motor response to advance information and were significantly disadvantaged by conditions requiring initiation of movement without a direct visual cue. There was also a significant negative correlation with age of disease onset and differing levels of advance information, suggesting an impact of FRDA on the development of motor cognition, independent of the effect of disease duration. We suggest that deficits are due to cerebellar impairment disrupting cerebro-ponto-cerebello-thalamo-cerebral loops (and thus cortical function), direct primary cortical pathology or a possible combination of the two.

The test of everyday attention reveals significant sustained volitional attention and working memory deficits in friedreich ataxia.

Sustained volitional attention and working memory capacity was examined for the first time in people with Friedreich ataxia (FRDA). We administered subtests of the Test of Everyday Attention to 16 individuals with molecularly confirmed FRDA and gender-, age-, and IQ-matched controls. Clinically significant impairment in working memory and sustained volitional attention was evident. Working memory deficits correlated significantly with GAA repeat number on the shorter allele of the FXN gene, and separately, with disease severity, as measured by the Friedreich Ataxia Rating Scale score. Sustained volitional attention was not correlated with disease parameters, suggesting that this impairment may not be related to the disease process in a simple way. The deficits observed may be the result of disruption to corticocerebellar pathways, or directly related to the cortical and/or cerebellar pathology evident in people with FRDA.

Near, yet so far: the effect of pictorial cues on spatial attention.

Distinct cognitive and neural mechanisms underlie perception and action in near (within-reach) and far (outside-reach) space. Objects in far space can be brought into the brain's near-space through tool-use. We determined whether a near object can be pushed into far space by changing the pictorial context in which it occurs. Participants (n = 372) made relative length judgements for lines presented in near space, but superimposed over photographs of near and far objects. The left segment of the line was overestimated in the baseline and near-context conditions whereas the right was overestimated in the far-context. The change from leftward to rightward overestimation is the same when lines are physically shifted from near to far space. Because participants did not have to do anything in relation to the photograph, the results suggest that simply viewing images with a near/far context can cause a shift of attention along the distal/proximal axis, which may reflect differential activation of the ventral/dorsal visual streams.

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 Huntington's 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.