Long-term Sustained Cognitive Benefits of Vagus Nerve Stimulation in Refractory Depression.

BACKGROUND: Treatment-resistant depression (TRD) is a serious chronic condition disabling patients functionally and cognitively. Chronic vagus nerve stimulation (VNS) is recognized for the management of TRD, but few studies have examined its long-term effects on cognitive dysfunction in unipolar and bipolar resistant depression. OBJECTIVE: The purpose of this study was to assess the course of cognitive functions and clinical symptoms in a cohort of patients treated with VNS for TRD. METHODS: In 14 TRD patients with VNS, standardized clinical and neuropsychological measures covering memory, attention/executive functions, and psychomotor speed were analyzed prestimulation and up to 2 years poststimulation. RESULTS: Vagus nerve stimulation patients significantly improved on cognitive and clinical measures. Learning and memory improved rapidly after 1 month of stimulation, and other cognitive functions improved gradually over time. Cognitive improvements were sustained up to 2 years of treatment. At 1 month, improvement in Montgomery-Åsberg Depression Rating Scale scores was not correlated with changes in any of the cognitive scores, whereas at 12 months, the change in Montgomery-Åsberg Depression Rating Scale score was significantly correlated with several measures (Stroop interference, verbal fluency, and Rey-Osterrieth Complex Figure delayed recall). CONCLUSIONS: In recent years, a growing interest in cognitive dysfunction in depression has emerged. Our results suggest that chronic VNS produces sustained clinical and cognitive improvements in TRD patients, with some mental functions improving as soon as 1 month after the initiation of the VNS therapy. Vagus nerve stimulation seems a very promising adjunctive therapy for TRD patients with cognitive impairment.

Oppositional behavior and longitudinal predictions of early adulthood mental health problems in chronic tic disorders.

Chronic tic disorders (TD) are associated with a number of psychological problems such as attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive behavior (OCB), oppositional-defiant disorder (ODD) as well as anxious and depressive symptoms. ODD is often considered a risk factor for many psychological symptoms and recent work suggests that different ODD dimensions show independent predictions of later psychological problems. This study examined the longitudinal predictions between ODD dimensions of Irritability and Defiance and the most frequent comorbidities in TD from childhood to early adulthood. From an initial sample of 135, parent reports were obtained on 58 participants with TD using standard clinical questionnaires and semi-structured interviews. Defiance symptoms decreased from baseline to follow-up whereas Irritability symptoms were more stable over time. In multiple regressions, Irritability in childhood predicted anxiety and OCB in early adulthood while Defiance in childhood predicted ADHD and conduct disorder symptoms in early adulthood. No developmental link was found for depressive symptoms. Results indicate that ODD dimensions are developmentally linked to both internalizing and externalizing adult mental health symptoms in TD.

A 6-Year Follow-up Study of Vagus Nerve Stimulation Effect on Quality of Life in Treatment-Resistant Depression: A Pilot Study.

OBJECTIVES: Treatment-resistant depression (TRD) carries a major burden on those affected by this disease and significantly impacts their quality of life (QOL). Vagus nerve stimulation (VNS) has showed promising results on symptoms, but its impact on QOL remains underresearched. This study aims to evaluate the long-term effects of VNS on both QOL and clinical symptoms for TRD patients, through a naturalistic 6-year follow-up. METHOD: Outpatients with confirmed TRD were enrolled to receive VNS. None of the patients enrolled left the study or was lost at follow-up. Patients were evaluated at 1, 3, 6, 12, 24, 36, 48, 60, and 72 months for a total of 10 assessments using the 36 item Short Form questionnaire, Hamilton Rating Scale for Depression and Hamilton Anxiety Rating Scale. RESULTS: Ten patients were enrolled with a mean age of 50 years. This study shows a clinically and statistically significant improvement of the mental QOL (P = 0.012), physical QOL (P < 0.002), depressive symptoms (P < 0.001), and anxiety symptoms (P < 0.001). CONCLUSIONS: This long-term naturalistic study is the first to demonstrate that the therapeutic effect of VNS on TRD goes beyond clinical symptoms to improve the daily QOL of those affected.

Response Inhibition in Tic Disorders: Waiting to Respond Is Harder When ADHD Is Present.

OBJECTIVE: Tic disorders such as Gilles-de-la-Tourette syndrome (TS) are associated with difficulties in withholding movements and sometimes inappropriate actions. The present study examined whether these disorders lead to a specific difficulty in withholding preprogrammed voluntary movements irrespective of decisions on whether or not to move. METHOD: Children with TS with or without attention-deficit hyperactivity disorder (ADHD) and controls performed a fast-paced simple reaction time task involving responses to a target in a rapid letter stream (9 letters/s, average foreperiod 332 ms) with feedback on response speed. RESULTS: The ADHD group showed more premature responses and more variable response time than other groups, whether the timing of the target was predictable or not. CONCLUSION: The data indicate that in tic disorders, the presence of ADHD is associated with difficulties in waiting to initiate preprogrammed movements independently of response selection or response timing difficulties.

Clinical features associated with an early onset in chronic tic disorders.

In chronic tic disorders such as Tourette syndrome (TS), tics often appear between 4 and 8 years but they can also appear in early childhood, a period in which symptom expression may be affected by early brain development. The present study examined whether symptom expression in early-onset TS was distinct from that observed in TS with a later onset. We compared the clinical characteristics in children with TS who developed tics before age 4 or after age 6. Early-onset TS was significantly associated with an increased rate of stuttering and other speech disfluencies as well as an increased rate of oppositional defiant disorder, symptoms that often appear before age 4. Early-onset TS was also linked to maternal transmission of tics. Early-onset TS was not significantly associated with tic severity, obsessive-compulsive behavior or attention-deficit hyperactivity disorder. The results suggest that an early onset affects symptom expression in tic disorders.

Effects of vagus nerve stimulation on pupillary function.

BACKGROUND: Chronic vagus nerve stimulation (VNS) is a recognized treatment for refractory epilepsy and depression. The vagus nerve projects to several brainstem autonomic structures. As pupillary measures are an easy and non-invasive method to evaluate autonomic functioning, we used resting diameter and light reflex measures to investigate the influence of VNS on the human central autonomic nervous system. METHOD: We studied 21 patients (7 with major depression, 14 with epilepsy) treated with chronic VNS (30s ON, 5 min OFF stimulation trains). Resting pupil size and light reflex measures were compared in consecutive intervals with (ON) and without stimulation (OFF). RESULTS: Compared to the OFF condition, the ON condition was associated with a significant increase in resting pupil diameter, but did not affect light reflex measures. There was no group difference between the two populations of patients (depression and epilepsy) on any of the pupil measures. CONCLUSION: VNS at clinically significant levels increases resting pupil diameter.

ODD irritability is associated with obsessive-compulsive behavior and not ADHD in chronic tic disorders.

Gilles de la Tourette syndrome (TS) and chronic tic disorder (CT) are often associated with a variety of behavioral comorbidities including attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive behavior (OCB), oppositional-defiant disorder (ODD) and temper outbursts. ODD is often associated with ADHD but its links to other symptoms of TS/CT is not as clear. This study examined whether the various symptoms of ODD were differentially linked to the various comorbidities in TS. A clinical sample of 135 children diagnosed with TS was evaluated through parent questionnaires and semi-structured interviews. Regressions and structural equation modeling confirmed that ODD is multidimensional in a TS/CT sample and showed that OCB was associated with the irritability symptoms of ODD whereas ADHD was associated with the Headstrong symptoms of ODD. Results suggest that increased attention to the different facets of ODD may help improve our understanding of emotional symptoms in TS/CT.

Bidirectional lexical-gustatory synesthesia.

In developmental lexical-gustatory synesthesia, specific words (inducers) can trigger taste perceptions (concurrents) and these synesthetic associations are generally stable. We describe a case of multilingual lexical-gustatory synesthesia for whom some synesthesias were bidirectional as some tastes also triggered auditory word associations. Evoked concurrents could be gustatory but also tactile sensations. In addition to words and pseudowords, many voices were effective inducers, suggesting increased connections between cortical taste areas and both voice-selective and language-selective areas. Lasting changes in some evoked tastes occurred during childhood suggesting that some plasticity can be present after the initial learning of associations. Inducers were often linked to taste concurrents phonologically or semantically, but also through identifiable childhood episodes (persons or events). Several inducers were phonologically linked to episodic inducers suggesting a process of secondary acquisition for many inducers. Implications of these observations are discussed.

Effects of a secondary task on postural control in children with Tourette syndrome.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by involuntary motor and vocal tics. Sub-clinical postural control anomalies have recently been reported in children with TS. The goal of the present study was to determine whether these anomalies interact with attention in postural control. Thirty-two younger (below 10 years) and 21 older (above 10 years) children with TS were compared to 13 younger and 15 older age-matched controls. Postural control was examined during standing with and without a secondary visual attention task. Sway velocity was higher in younger children than older ones and also higher in children with TS than in controls. The secondary task exacerbated the velocity anomalies in younger children with TS. The effects were independent of tic severity, medication, and attention deficit. The results suggest that postural control anomalies in TS are sensitive to attentional requirements.

Association of intronic variants of the BTBD9 gene with Tourette syndrome.

OBJECTIVE: To test the association between Tourette syndrome (TS) and genetic variants in genomic loci MEIS1, MAP2K5/LBXCOR1, and BTBD9, for which genome-wide association studies in restless legs syndrome and periodic limb movements during sleep revealed common risk variants. DESIGN: Case-control association study. SETTING: Movement disorder clinic in Montreal. Subjects We typed 14 single-nucleotide polymorphisms spanning the 3 genomic loci in 298 TS trios, 322 TS cases (including 298 probands from the cohort of TS trios), and 290 control subjects. MAIN OUTCOME MEASURES: Clinical diagnosis of TS, obsessive-compulsive disorder, and attention-deficit disorder. RESULTS: The study provided 3 single-nucleotide polymorphisms within BTBD9 associated with TS (chi(2) = 8.02 [P = .005] for rs9357271), with the risk alleles for restless legs syndrome and periodic limb movements during sleep overrepresented in the TS cohort. We stratified our group of patients with TS according to presence or absence of obsessive-compulsive disorder and/or attention-deficit disorder and found that variants in BTBD9 were strongly associated with TS without obsessive-compulsive disorder (chi(2) = 12.95 [P < .001] for rs9357271). Furthermore, allele frequency of rs9357271 inversely correlated with severity of obsessive-compulsive disorder as measured by the Yale-Brown Obsessive Compulsive Scale score. CONCLUSION: Variants in BTBD9 that predispose to restless legs syndrome and periodic limb movements during sleep are also associated with TS, particularly TS without obsessive-compulsive disorder.

Movement irregularities in atypical parkinsonian syndromes.

This study examined discrete motor irregularities in ballistic aiming movements in patients with atypical parkinsonian syndromes (APS). Nine patients with APS were compared to 9 patients with idiopathic Parkinson's disease (PD) and 9 controls on ballistic arm extension movements performed on a digitizing tablet without visual feedback and without accuracy constraints. Patients with APS showed a higher number of irregularities in the acceleration and jerk time series compared to PD patients and controls. No difference was found between PD patients and controls. These discrete irregularities were not associated with general motor impairment, tremor, akinesia, or rigidity. These results suggest that atypical parkinsonism is associated with movement irregularities in ballistic movements, which may help differentiate APS from PD.

Psychopharmacology of tic disorders.

INTRODUCTION: Tics disorders and Tourette syndrome are commonly encountered in clinical practice. Currently, a vast number of behavioural, pharmacological and surgical treatments are available. METHODS: Relevant and recent articles about clinical features, neurobiology and treatment of tic disorders and Tourette syndrome were reviewed and summarized. RESULTS: Tic disorders and Tourette syndrome are frequently associated with comorbid conditions such as obsessive compulsive symptoms, attention deficit and hyperactivity disorder, anxiety and depression, behavioural disorders and sleep difficulties. Fronto-striatal circuits and the dopaminergic system are believed to be involved in the pathophysiology of TS and tics. Pharmacological options that have been studied for treatment of tic disorders are reviewed. Behavioural therapy such as habit reversal training, and surgical treatment are other options. It is essential to identify and address comorbid conditions such as attention deficit disorder, obsessive-compulsive symptoms, depression, behavioural disorders and sleep disturbances, as they often cause more distress and disability than the tics themselves. CONCLUSION: Tic disorders frequently do not require pharmacological treatment, but if required, first line treatment options include dopamine modulators, tetrabenazine, clonidine and behavioural therapy.

Huntington's disease affects movement termination.

Huntington's disease (HD) is a neurodegenerative disease affecting the striatum and associated with deficits in voluntary movement in early stages. The final portion of aiming movements is particularly affected in HD and one hypothesis is that this deficit is linked to attention or terminal control requirements. Sixteen patients with early HD and 16 age-matched controls were examined in aiming movements. Four conditions manipulated movement termination requirements (discrete movements with a complete stop vs. cyclical back-and-forth movements) and the presence of flankers around the target. Reducing movement termination requirements significantly attenuated deficits in the final movement phase in patients. The presence of flankers around the target affected the initial portion of movements but did not affect the two groups differentially. These results indicate that terminal control requirements affect voluntary movements in HD. This suggests that frontostriatal systems are involved in movement termination.

Episodic memory impairment in Huntington's disease: a meta-analysis.

Memory dysfunction is an important feature in the clinical presentation of Huntington's disease (HD) and may precede the onset of motor symptoms. Although several studies have contributed to the quantitative and qualitative description of memory impairments in HD, the characterization of episodic memory impairments has varied considerably. Whereas most studies report significant impairments on free recall tests, performance on recognition tests has been considerably more variable, ranging from normal to markedly deficient. This absence of a well-established recognition memory deficit has led some investigators to attribute the memory deficits in HD to a retrieval-based episodic memory impairment. We felt that a quantitative review of the literature was needed to better characterize these episodic memory impairments. We conducted a meta-analysis to assess the magnitude of the recognition memory deficit in HD and to examine it in relation to the known deficit in recall. Memory data were provided by 544 symptomatic HD patients, 224 presymptomatic gene-carriers, and 963 control subjects. The overall group comparison between symptomatic patients and controls yielded effect sizes of d=1.95 for free recall and d=1.73 for recognition. We split the symptomatic group into two subgroups based on their mental status (mild and moderate/severe dementia) and both showed significant deficits in recall and recognition memory, though recall was more impaired than recognition in the mild dementia subgroup. Only slight memory impairment was observed in the presymptomatic subjects. The results show that deficits in recognition memory must be accounted for in future models of memory impairment in HD.

New object onsets reduce conscious access to unattended targets.

Attention to a visual target can affect perception of a subsequent target for half a second, increasing its sensitivity to backward masking (the attentional blink, AB). In 6 studies, we compared the AB when the second target and its mask had a common onset and when the mask appeared after the target. The results indicate that common-onset masks do not produce large ABs even when there is a feature change or an interruption of the mask after the target but do produce a large AB if the location of the mask is changed. The data suggest that new object onsets reduce conscious access to unattended targets.

Chromosome 11-q24 region in Tourette syndrome: association and linkage disequilibrium study in the French Canadian population.

Previous studies have found association and linkage between Tourette syndrome (TS) and markers at the 11q24 region, mainly with markers D11S1377 and D11S933. In order to determine if these positive findings could be replicated in our sample, we undertook a family-based association study in 199 French Canadian TS nuclear families. We genotyped 572 individuals from 174 complete and 25 incomplete TS trios. TDT analysis failed to detect an association between TS and six markers from 11q24. Furthermore, no haplotype combining alleles from D11S1377, D11S933, or any of the other four markers was associated with the disorder. Linkage disequilibrium analysis showed evidence of historical recombination between every contiguous pair of markers, indicating that these genetic variants are probably in equilibrium in the French Canadian population. Further analysis in additional families, with different methodologies (linkage and association) will be required in order to determine if the 11q24 region harbors a susceptibility locus for TS. If it does, this defect may not be frequent in the French Canadian population due to locus heterogeneity.

Standardization of quantitative tests for preclinical detection of neuromotor dysfunctions in pediatric neurotoxicology.

In the neurotoxicology pediatric domain, few neuromotor tests are specifically designed to be sensitive enough for the early detection of subtle deficits in voluntary and involuntary movements. In research and clinical domains, an effort is done to objectify or quantify the qualitative aspects of a movement (pattern of movement) in predicting neurological problems. This study aimed to standardize quantitative motor measures initially developed for adults and adapted to the evaluation of preschoolers. The sample consisted of 110 healthy children aged 4-6. The following quantitative neuromotor tests were selected: alternating movements and pointing movements (DOCO Microsystèmes Inc., Montréal, Canada), postural tremor, postural sway and simple reaction time (Danish Product Development Ltd., Snekkersten, Denmark). Validation measures included global motor tasks and a neurological examination. Results indicate adequate test-retest reliability and complementarities amongst the selected voluntary and involuntary measures. Both the feasibility and relevance of quantitative neuromotor tests in preschool aged children were established. Results also provide a representation of intra-individual and inter-individual variability within this population. Lastly, the results highlight the importance of developmental factors, behavioral factors and testing conditions in the neuromotor evaluation of young children. The proposed tests could help in the early detection of children at risk for motor dysfunctions following neurotoxic exposure. The tests can also be used for the follow up of various conditions relating to motor functions (cerebral palsy, muscular dystrophy, preterm infants) and in the evaluation of the effects of medication.

Early Huntington's disease affects movements in transformed sensorimotor mappings.

This study examined the effect of transformed visual feedback on movement control in Huntington's disease (HD). Patients in the early stages of HD and controls performed aiming movements towards peripheral targets on a digitizing tablet and emphasizing precision. In a baseline condition, HD patients were slower but showed few precision problems in aiming. When visual feedback was inverted in both vertical and horizontal axes, patients showed problems in initial and terminal phases of movement where feedback is most critical. When visual feedback was inverted along a single axis as in a mirror-inversion, HD patients showed large deviations and over-corrections before adaptation. Adaptation was similar in both groups. These results suggest that HD impairs on-line error correction in novel movements.

Neuromotor functions in Inuit preschool children exposed to Pb, PCBs, and Hg.

The aim of this study was to examine the effects of prenatal and postnatal chronic exposure to mercury (Hg), polychlorinated biphenyls (PCBs) and lead (Pb) on the neuromotor development of preschool children. The study population consisted of 110 preschool Inuit children from Nunavik (Canada). Blood Hg, PCBs and Pb concentrations were measured at birth (cord blood) and at the time of testing. Gross motor functions were evaluated and a neurological examination was performed. Fine neuromotor performance was assessed using quantitative measures of postural hand tremor, reaction time, sway oscillations, as well as alternating and pointing movements. Potential covariates were documented including demographic and familial characteristics, other prenatal neurotoxicants (alcohol, tobacco) and nutrients (selenium (Se), Omega-3 polyunsaturated fatty acids (n-3 PUFA)). Hierarchical multivariate regression analyses were performed, controlling for significant covariates. Gross motor development was not linked to prenatal exposures. However, significant associations were observed between blood Pb concentration at testing time and changes in reaction time, sway oscillations, alternating arm movements and action tremor. For some of these outcomes, neuromotor effects of Pb exposure are observed at blood concentrations below 10 microg/dl. Negative effects of PCBs on neuromotor development were not clearly observed, neither were the potential beneficial effects of n-3 PUFA and selenium. Tremor amplitude was related to blood Hg concentrations at testing time, which corroborate an effect already reported among adults.