Exploring the impact of intensified multiple session tDCS over the left DLPFC on brain function in MCI: a randomized control trial.

Transcranial direct current stimulation combined with cognitive training (tDCS-cog) represents a promising approach to combat cognitive decline among healthy older adults and patients with mild cognitive impairment (MCI). In this 5-day-long double-blinded randomized trial, we investigated the impact of intensified tDCS-cog protocol involving two trains of stimulation per day on working memory (WM) enhancement in 35 amnestic and multidomain amnestic MCI patients. Specifically, we focused to improve WM tasks relying on top-down attentional control and hypothesized that intensified tDCS would enhance performance of visual object matching task (VOMT) immediately after the stimulation regimen and at a 1-month follow-up. Secondarily, we explored whether the stimulation would augment online visual working memory training. Using fMRI, we aimed to elucidate the neural mechanisms underlying the intervention effects by analyzing BOLD activations during VOMT. Our main finding revealed no superior after-effects of tDCS-cog over the sham on VOMT among individuals with MCI as indicated by insignificant immediate and long-lasting after-effects. Additionally, the tDCS-cog did not enhance online training as predicted. The fMRI analysis revealed brain activity alterations in right insula that may be linked to tDCS-cog intervention. In the study we discuss the insignificant behavioral results in the context of the current evidence in tDCS parameter space and opening the discussion of possible interference between trained cognitive tasks.

Cognitive Aftereffects of Acute tDCS Coupled with Cognitive Training: An fMRI Study in Healthy Seniors.

Enhancing cognitive functions through noninvasive brain stimulation is of enormous public interest, particularly for the aging population in whom processes such as working memory are known to decline. In a randomized double-blind crossover study, we investigated the acute behavioral and neural aftereffects of bifrontal and frontoparietal transcranial direct current stimulation (tDCS) combined with visual working memory (VWM) training on 25 highly educated older adults. Resting-state functional connectivity (rs-FC) analysis was performed prior to and after each stimulation session with a focus on the frontoparietal control network (FPCN). The bifrontal montage with anode over the left dorsolateral prefrontal cortex enhanced VWM accuracy as compared to the sham stimulation. With the rs-FC within the FPCN, we observed significant stimulation × time interaction using bifrontal tDCS. We found no cognitive aftereffects of the frontoparietal tDCS compared to sham stimulation. Our study shows that a single bifrontal tDCS combined with cognitive training may enhance VWM performance and rs-FC within the relevant brain network even in highly educated older adults.

DNAJC13 p.Asn855Ser mutation screening in Parkinson's disease and pathologically confirmed Lewy body disease patients.

BACKGROUND: Recently, a novel mutation in exon 24 of DNAJC13 gene (p.Asn855Ser, rs387907571) has been reported to cause autosomal dominant Parkinson's disease (PD) in a multi-incident Mennonite family. METHODS: In the present study the mutation containing exon of the DNAJC13 gene has been sequenced in a Caucasian series consisting of 1938 patients with clinical PD and 838 with pathologically diagnosed Lewy body disease (LBD). RESULTS: Our sequence analysis did not identify any coding variants in exon 24 of DNAJC13. Two previously described variants in intron 23 (rs200204728 and rs2369796) were observed. CONCLUSION: Our results indicate that the region surrounding the DNAJC13 p.Asn855Ser substitution is highly conserved and mutations in this exon are not a common cause of PD or LBD among Caucasian populations.

Acoustic evaluation of short-term effects of repetitive transcranial magnetic stimulation on motor aspects of speech in Parkinson's disease.

Hypokinetic dysarthria in Parkinson's disease (PD) can be characterized by monotony of pitch and loudness, reduced stress, variable rate, imprecise consonants, and a breathy and harsh voice. Using acoustic analysis, we studied the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) applied over the primary orofacial sensorimotor area (SM1) and the left dorsolateral prefrontal cortex (DLPFC) on motor aspects of voiced speech in PD. Twelve non-depressed and non-demented men with PD (mean age 64.58 ± 8.04 years, mean PD duration 10.75 ± 7.48 years) and 21 healthy age-matched men (a control group, mean age 64 ± 8.55 years) participated in the speech study. The PD patients underwent two sessions of 10 Hz rTMS over the dominant hemisphere with 2,250 stimuli/day in a random order: (1) over the SM1; (2) over the left DLPFC in the "on" motor state. Speech examination comprised the perceptual rating of global speech performance and an acoustic analysis based upon a standardized speech task. The Mann-Whitney U test was used to compare acoustic speech variables between controls and PD patients. The Wilcoxon test was used to compare data prior to and after each stimulation in the PD group. rTMS applied over the left SM1 was associated with a significant increase in harmonic-to-noise ratio and net speech rate in the sentence tasks. With respect to the vowel task results, increased median values and range of Teager-Kaiser energy operator, increased vowel space area, and significant jitter decrease were observed after the left SM1 stimulation. rTMS over the left DLPFC did not induce any significant effects. The positive results of acoustic analysis were not reflected in a subjective rating of speech performance quality as assessed by a speech therapist. Our pilot results indicate that one session of rTMS applied over the SM1 may lead to measurable improvement in voice quality and intensity and an increase in speech rate and tongue movements. Nevertheless, these changes were not accompanied by changes in a perceptual evaluation of speech performance by a speech therapist. Future placebo-controlled studies in larger patient cohorts should verify if rTMS would be clinically useful for treating hypokinetic dysarthria in PD.

The role of the right dorsolateral prefrontal cortex in the Tower of London task performance: repetitive transcranial magnetic stimulation study in patients with Parkinson's disease.

We studied whether one session of high-frequency repetitive transcranial magnetic stimulation (rTMS) applied over either the right or left dorsolateral prefrontal cortex would induce any measurable changes in the Tower of London spatial planning task performance in patients with Parkinson's disease (PD). Ten patients with PD (with no dementia and/or depression) entered the randomized, sham-stimulation-controlled study with a crossover design. Active and placebo rTMS were applied over either the left or the right dorsolateral prefrontal cortex (in four separate sessions) in each patient. The order of sessions was randomized. The Tower of London task was performed prior to and immediately after each appropriate session. The "total problem-solving time" was our outcome measure. Only active rTMS of the right dorsolateral prefrontal cortex induced significant enhancement of the total problem-solving time, p = 0.038. Stimulation of the left prefrontal cortex or sham stimulations induced no significant effects. Only rTMS applied over the right dorsolateral prefrontal cortex induced positive changes in the spatial planning task performance in PD, which further supports the results of functional imaging studies indicating the causal engagement of the right-sided hemispheric structures in solving the task in this patient population.

EFNS-ENS Guidelines on the diagnosis and management of disorders associated with dementia.

BACKGROUND AND OBJECTIVES: The last version of the EFNS dementia guidelines is from 2007. In 2010, the revised guidelines for Alzheimer's disease (AD) were published. The current guidelines involve the revision of the dementia syndromes outside of AD, notably vascular cognitive impairment, frontotemporal lobar degeneration, dementia with Lewy bodies, corticobasal syndrome, progressive supranuclear palsy, Parkinson's disease dementia, Huntington's disease, prion diseases, normal-pressure hydrocephalus, limbic encephalitis and other toxic and metabolic disorders. The aim is to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists and other specialist physicians responsible for the care of patients with dementing disorders. It represents a statement of minimum desirable standards for practice guidance. METHODS: The task force working group reviewed evidence from original research articles, meta-analyses and systematic reviews, published by June 2011. The evidence was classified (I, II, III, IV) and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. RESULTS AND CONCLUSIONS: New recommendations and good practice points are made for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers. All recommendations were revised as compared with the previous EFNS guidelines. The specialist neurologist together with primary care physicians play an important role in the assessment, interpretation and treatment of symptoms, disability and needs of dementia patients.

Default mode network and extrastriate visual resting state network in patients with Parkinson's disease dementia.

AIMS: Using fMRI, we evaluated the default mode network (DMN) and the extrastriate visual resting state network (ESV-RSN) in 14 patients with Parkinson's disease dementia (PDD) as compared with 18 patients with Parkinson's disease (PD) without dementia and 18 healthy controls (HC). METHODS: We analyzed the seed-based functional connectivity of both resting state data and deactivations during a visual complex scene-encoding task. RESULTS: Using the posterior cingulate cortex/precuneus as a seed for the DMN analysis, we observed significant decreases of connectivity in the right inferior frontal gyrus in PDD as compared to PD and HC. Using the caudate nucleus as a seed for the ESV-RSN analysis, we found significant decreases of connectivity in the left and right inferior occipital gyrus in PDD as compared to HC. CONCLUSION: Differences in functional connectivity patterns between PDD and PD/HC were observed in areas known to be engaged in stimulus-driven reorienting of attention and in visual processing.

Functional neuroanatomy of vocalization in patients with Parkinson's disease.

UNLABELLED: In Parkinson's disease (PD) both speech production and self-monitoring of voiced speech are altered. METHODS: In our previous study we used functional magnetic resonance imaging (fMRI) to examine which brain areas are involved in overt reading in nine female PD patients (mean age 66.0 ± 11.6 years) compared with eight age-matched healthy female controls (mean age 62.2 years ± 12.3). Here we performed the post-hoc seed-based functional connectivity analysis of our data to assess the functional connectivity between the periaqueductal gray matter (PAG; i.e. the core subcortical structure involved in human vocalization) and other brain regions in the same groups of PD patients and controls. RESULTS: In PD patients as compared with controls we observed increased connectivity between PAG and basal ganglia, posterior superior temporal gyrus, supramarginal and fusiform gyri and inferior parietal lobule on the right side. In the PD group, the connectivity strength in the right putamen and the right sypramarginal gyrus was correlated with variability of pitch while the connectivity strength in the right posterior superior temporal gyrus and in the right inferior parietal lobule was correlated with speech loudness. CONCLUSION: We observed functional reorganization in PD patients as compared with controls in both the motor basal ganglia-thalamo-cortical circuitry and cortical areas known to be engaged in-auditory and somatosensory feedback control of voiced speech. These changes were hemisphere-specific and might either reflect effects of dopaminergic treatment or at least partially successful compensatory mechanisms involved in early-stage PD.

Dementia after DBS Surgery: A Case Report and Literature Review.

We report the case history of a 75-year-old woman with Parkinson's disease who developed severe cognitive problems after deep brain stimulation (DBS) of the bilateral subthalamic nuclei (STN). After a brief cognitive improvement, the patient gradually deteriorated until she developed full-blown dementia. We discuss the case with respect to the cognitive effects of STN DBS and the possible risk factors of dementia after STN DBS surgery.

Instrumental activities of daily living in Parkinson's disease dementia as compared with Alzheimer's disease: relationship to motor disability and cognitive deficits: a pilot study.

OBJECTIVE: Our objective was to assess which clinical factors contribute most to the impairment of instrumental activities of daily living (IADL) in patients with dementia in Parkinson's disease (PDD) as compared to age- and dementia duration-matched patients with Alzheimer's disease (AD). METHODS: Eighteen consecutive subjects (16 men, 2 women) with PDD and 30 age- and dementia duration-matched subjects with AD (13 men, 17 women) were recruited. The groups were not matched for their Mini-Mental Status Examination (MMSE) score. Neuropsychiatric, cognitive and motor data were collected in a routine clinical setting using the MMSE, four brief tests of the seven minute screen (i.e. the Benton Temporal Orientation, Grober and Buschke's enhanced cued recall, verbal fluency, and the clock drawing test), the Neuropsychiatric Inventory, a modified version of the Hoehn and Yahr scale and a Czech modified version of Lawton's IADL questionnaire. The IADL scores were correlated with clinical variables in each group. RESULTS: There were no differences in IADL abilities between both groups. A significant association was found between IADL and cognitive impairment as measured by screening tests in the AD group. In the PDD group, IADL scores were particularly correlated with PD duration (r=-0.73, p<0.01) and the Hoehn and Yahr score (r=-0.59, p<0.01). CONCLUSION: Our pilot study results show that motor deficits remain the major contributor to IADL impairment in PDD.

EFNS guidelines for the diagnosis and management of Alzheimer's disease.

BACKGROUND AND OBJECTIVES: In 2008 a task force was set up to develop a revision of the European Federation of the Neurological Societies (EFNS) guideline for the diagnosis and management of Alzheimer's disease (AD) and other disorders associated with dementia, published in early 2007. The aim of this revised international guideline was to present a peer-reviewed evidence-based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists, and other specialist physicians responsible for the care of patients with AD. Mild cognitive impairment and non-Alzheimer dementias are not included in this guideline. METHODS: The task force working group reviewed evidence from original research articles, meta-analysis, and systematic reviews, published before May 2009. The evidence was classified and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided. RESULTS: The recommendations for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of AD, behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers were all revised as compared with the previous EFNS guideline. CONCLUSION: A number of new recommendations and good practice points are made, namely in CSF, neuropsychology, neuroimaging and reviewing non-evidence based therapies. The assessment, interpretation, and treatment of symptoms, disability, needs, and caregiver stress during the course of AD require the contribution of many different professionals. These professionals should adhere to these guideline to improve the diagnosis and management of AD.

The effect of cortical repetitive transcranial magnetic stimulation on cognitive event-related potentials recorded in the subthalamic nucleus.

We studied whether the cognitive event-related potentials (ERP) in the subthalamic nucleus (STN) are modified by the modulation of the inferior frontal cortex (IFC) and the dorsolateral prefrontal cortex (DLPFC) with repetitive transcranial magnetic stimulation (rTMS). Eighteen patients with Parkinson's disease who had been implanted with a deep brain stimulation (DBS) electrode were included in the study. The ERPs were recorded from the DBS electrode before and after the rTMS (1 Hz, 600 pulses) over either the right IFC (10 patients) or the right DLPFC (8 patients). The ERPs were generated by auditory stimuli. rTMS over the right IFC led to a shortening of ERP latencies from 277 +/- 14 ms (SD) to 252 +/- 19 ms in the standard protocol and from 296 +/- 17 ms to 270 +/- 20 ms in the protocol modified by a higher load of executive functions (both P < 0.01). The application of rTMS over the DLPFC and the sham stimulation over the IFC showed no significant changes. The shortening of ERP latency after rTMS over the right IFC reflected the increase in the speed of the cognitive process. The rTMS modulation of activity of the DLPFC did not influence the ERP. Connections (the IFC-STN hyperdirect pathway) with the cortex that bypass the BG-thalamocortical circuitries could explain the position of the STN in the processing of executive functions.

Serum inflammatory biomarkers in Parkinson's disease.

Numerous recent findings indicate the involvement of a neuroinflammatory reaction in the neurodegeneration in idiopathic Parkinson's disease (PD). We examined 29 consecutive patients with PD, ages 54-84 years, most of whom were moderately impaired (median UPDRS 19; Hoehn-Yahr 3; MMSE 28). A series of serum biomarkers were investigated, and their levels were correlated with the degree of the motor and cognitive impairment. There were no abnormalities of IL-6, acute phase proteins (C-reactive protein, serum amyloid A, alpha 1-antitrypsin, orosomucoid, ceruloplasmin, alpha 2-macroglobulin, transferrin, prealbumin) and factors of the complement system (C1q, C1-INH, C3, C4). A decrease in Mannan-binding lectin (MBL) levels was observed in six patients; an elevation of tumor necrosis factor-alpha (TNF-alpha) was found in 12 patients. No statistically significant correlation was found between the patient's clinical state (neuropsychologic and motor, as expressed by UPDRS III, Hoehn-Yahr, and MMSE) and the immunomarker changes. Our results indicate that the inflammatory process may be reflected in the serum; nevertheless, further research is needed to elucidate the possible clinical implications.

Dorsolateral prefrontal cortex: a possible target for modulating dyskinesias in Parkinson's disease by repetitive transcranial magnetic stimulation.

We studied whether five sessions of 10 Hz repetitive transcranial magnetic stimulation (rTMS treatment) applied over the dorsolateral prefrontal cortex (DLPFC) or the primary motor cortex (MC) in advanced Parkinson's disease (PD) patients would have any effect on L-dopa-induced dyskinesias and cortical excitability. We aimed at a randomised, controlled study. Single-pulse transcranial magnetic stimulation (TMS), paired-pulse transcranial magnetic stimulation, and the Unified Parkinson's Disease Rating Scale (UPDRS parts III and IV) were performed prior to, immediately after, and one week after an appropriate rTMS treatment. Stimulation of the left DLPFC induced a significant motor cortex depression and a trend towards the improvement of L-dopa-induced dyskinesias.

Amyotrophic lateral sclerosis and Alzheimer's disease--clinical and neuropathological considerations in two cases.

Amyotrophic lateral sclerosis (ALS) may be accompanied by cognitive impairment; when present, it is mainly in the form of frontotemporal impairment. We report on two cases with clinically defined ALS that subsequently developed dementia. Neuropathological examination showed not only the typical neuropathological hallmarks characteristic of ALS but, surprisingly, also showed neurofibrillary tangles and neuritic plaques in sufficient numbers to fulfill the diagnostic criteria of definite Alzheimer's disease.

Anterior opercular syndrome in frontotemporal lobar degeneration with ubiquitin-only immunoreactive neuronal changes.

This paper presents for the first time an anterior opercular syndrome in association with a gait disorder, dropped head syndrome, dysphagia, and sialorrhea in a neuropathologically proven case of frontotemporal lobar degeneration with ubiquitin inclusions.

An event-related fMRI study of self-paced alphabetically ordered writing of single letters.

The spatial location of activation for writing individual letters and for writing simple dots was studied using event-related functional MRI. Ten healthy right-handed subjects were scanned while performing two different protocols with self-paced repetitive movement. In the first protocol with self-paced dot writing, we observed significant activation in regions known to participate in motor control: contralateral to the movement in the primary sensorimotor and supramarginal cortices, the supplementary motor area (SMA) with the underlying cingulate, in the thalamus and, to a lesser extent, in the ipsilateral inferior parietal and occipital cortices. In the second protocol, we investigated an elemental writing feature--writing single letters. We observed statistically significant changes in the premotor, sensorimotor and supramarginal cortices, the SMA and the thalamus with left predominance, and in the bilateral premotor and inferior/superior parietal cortices. The parietal region that was active during the writing of single letters spanned the border between the parietal superior and inferior lobuli Brodmann area (BA 2, 40), deep in the intraparietal sulcus, with a surprising right-sided dominance. The direct comparison of the results of the two protocols was not significant with a confidence level of P<0.05 corrected for whole brain volume. Thus, the ROI approach was used, and we tried to find significant differences within the two predefined regions of interest (ROI) (BA 7, BA 37). The differences were found with a confidence level of P<0.05 corrected for the volume of these predicted areas. The ROI were located in the posterior parts of hemispheres, in the ventral and in the dorsal visual pathway. The right-sided posterior cortices may play a role in the elemental mechanisms of writing. It is possible that activation of this region is linked with the spatial dimension of the writing.

Cognitive functioning after repetitive transcranial magnetic stimulation in patients with cerebrovascular disease without dementia: a pilot study of seven patients.

AIMS: Examine whether one session of high frequency repetitive transcranial magnetic stimulation (rTMS) applied over the left dorsolateral prefrontal cortex (DLPFC) would induce any measurable cognitive changes in patients with cerebrovascular disease and mild cognitive deficits. PATIENTS AND METHOD: Seven patients with cerebrovascular disease and mild executive dysfunction entered the randomised, controlled, blinded study with a crossover design. rTMS was applied either over the left DLPFC (an active stimulation site) or over the left motor cortex (MC; a control stimulation site) in one session. Each patient participated in both stimulation sessions (days 1 and 4) and the order of stimulation sites (DLPFC or MC) was randomised. A short battery of neuropsychological tests was performed by a blinded psychologist prior to and after each rTMS session. Psychomotor speed, executive function, and memory were evaluated. RESULTS: The only mild but significant stimulation site-specific effect of rTMS was observed in the Stroop interference results (i.e. improvement) after the stimulation of DLPFC but not MC in comparison with the baseline scores (Wilcoxon, Z=-2.03, p=0.04). Patients improved in the digit symbols subtest of the Wechsler adult intelligence scale-revised after both rTMS sessions regardless of the stimulation site (DLPFC or MC; Z=-2.06, p=0.04 and Z=-2.06, p=0.04, respectively). There was no measurable effect of rTMS in any other neuropsychological test. CONCLUSION: Our pilot study results showed that one session of the high frequency rTMS applied over the left DLPFC was safe in patients with cerebrovascular disease and mild executive deficits, and may induce measurable positive effects on executive functioning.

Cognitive performance in people with Parkinson's disease and mild or moderate depression: effects of dopamine agonists in an add-on to L-dopa therapy.

In a randomized prospective multi-centre study, we evaluated the cognitive performances of a group of 41 non-demented patients, all with advanced Parkinson's disease (PD) and a current depressive episode, in whom the effects of pramipexole (PPX) and pergolide (PRG) in an add-on to l-dopa therapy were also studied and published with regard to motor symptoms of PD, motor complications and depression. The Trail Making Test, the Stroop test and four subtests (arithmetic, picture completion, digit symbols and similarities) of the Wechsler Adult Intelligence Scale-Revised were performed prior to and 8 months after the administration of either PPX or PRG. We found no statistically significant difference between the two tested drugs or between the first and the last visit in any of the above-listed neuropsychological tests. All patients' motor outcomes significantly improved and we conclusively demonstrated the anti-depressive effect of PPX. The dissociation of dopaminomimetic effects on the different tested domains indicates that there are different pathological mechanisms of cognitive, motor and affective disturbances in advanced PD patients. In our non-demented group of fluctuating depressed PD subjects, both PPX and PRG administration in combination with l-dopa were safe in terms of the effect on cognitive performance.