Transcranial direct current stimulation of the right temporoparietal junction facilitates hippocampal spatial learning in Alzheimer's disease and mild cognitive impairment.

OBJECTIVE: Spatial memory deficits are an early symptom in Alzheimer's disease (AD), reflecting the neurodegenerative processes in the neuronal navigation network such as in hippocampal and parietal cortical areas. As no effective treatment options are available, neuromodulatory interventions are increasingly evaluated. Against this backdrop, we investigated the neuromodulatory effect of anodal transcranial direct current stimulation (tDCS) on hippocampal place learning in patients with AD or mild cognitive impairment (MCI). METHODS: In this randomized, double-blind, sham-controlled study with a cross-over design anodal tDCS of the right temporoparietal junction (2 mA for 20 min) was applied to 20 patients diagnosed with AD or MCI and in 22 healthy controls while they performed a virtual navigation paradigm testing hippocampal place learning. RESULTS: We show an improved recall performance of hippocampal place learning after anodal tDCS in the patient group compared to sham stimulation but not in the control group. CONCLUSIONS: These results suggest that tDCS can facilitate spatial memory consolidation via stimulating the parietal-hippocampal navigation network in AD and MCI patients. SIGNIFICANCE: Our findings suggest that tDCS of the temporoparietal junction may restore spatial navigation and memory deficits in patients with AD and MCI.

The spectrum of progressive multifocal leukoencephalopathy: a practical approach.

John Cunningham virus (JCV) infection of the central nervous system causes progressive multifocal leukoencephalopathy (PML) in patients with systemic immunosuppression. With the increased application of modern immunotherapy and biologics in various immune-mediated disorders, the PML risk spectrum has changed. Thus, new tools and strategies for risk assessment and stratification in drug-associated PML such as the JCV antibody indices have been introduced. Imaging studies have highlighted atypical presentations of cerebral JCV disease such as granule cell neuronopathy. Imaging markers have been developed to differentiate PML from new multiple sclerosis lesions and to facilitate the early identification of pre-clinical manifestations of PML and its immune reconstitution inflammatory syndrome. PML can be diagnosed either by brain biopsy or by clinical, radiographic and virological criteria. Experimental treatment options including immunization and modulation of interleukin-mediated immune response are emerging. PML should be considered in any patient with compromised systemic or central nervous system immune surveillance presenting with progressive neurological symptoms.

The hippocampus in aging and disease: From plasticity to vulnerability.

The hippocampus has a pivotal role in learning and in the formation and consolidation of memory and is critically involved in the regulation of emotion, fear, anxiety, and stress. Studies of the hippocampus have been central to the study of memory in humans and in recent years, the regional specialization and organization of hippocampal functions have been elucidated in experimental models and in human neurological and psychiatric diseases. The hippocampus has long been considered a classic model for the study of neuroplasticity as many examples of synaptic plasticity such as long-term potentiation and -depression have been identified and demonstrated in hippocampal circuits. Neuroplasticity is the ability to adapt and reorganize the structure or function to internal or external stimuli and occurs at the cellular, population, network or behavioral level and is reflected in the cytological and network architecture as well as in intrinsic properties of hippocampal neurons and circuits. The high degree of hippocampal neuroplasticity might, however, be also negatively reflected in the pronounced vulnerability of the hippocampus to deleterious conditions such as ischemia, epilepsy, chronic stress, neurodegeneration and aging targeting hippocampal structure and function and leading to cognitive deficits. Considering this framework of plasticity and vulnerability, we here review basic principles of hippocampal anatomy and neuroplasticity on various levels as well as recent findings regarding the functional organization of the hippocampus in light of the regional vulnerability in Alzheimer's disease, ischemia, epilepsy, neuroinflammation and aging.

Imaging of autoimmune encephalitis--Relevance for clinical practice and hippocampal function.

The field of autoimmune encephalitides associated with antibodies targeting cell-surface antigens is rapidly expanding and new antibodies are discovered frequently. Typical clinical presentations include cognitive deficits, psychiatric symptoms, movement disorders and seizures and the majority of patients respond well to immunotherapy. Pathophysiological mechanisms and clinical features are increasingly recognized and indicate hippocampal dysfunction in most of these syndromes. Here, we review the neuroimaging characteristics of autoimmune encephalitides, including N-methyl-d-aspartate (NMDA) receptor, leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2) encephalitis as well as more recently discovered and less frequent forms such as dipeptidyl-peptidase-like protein 6 (DPPX) or glycine receptor encephalitis. We summarize findings of routine magnetic resonance imaging (MRI) investigations as well as (18)F-fluoro-2-deoxy-d-glucose (FDG)-positron emission tomography (PET) and single photon emission tomography (SPECT) imaging and relate these observations to clinical features and disease outcome. We furthermore review results of advanced imaging analyses such as diffusion tensor imaging, volumetric analyses and resting-state functional MRI. Finally, we discuss contributions of these neuroimaging observations to the understanding of the pathophysiology of autoimmune encephalitides.

Voxel seed coherent source analysis on transient global amnesia patients.

Transient global amnesia (TGA) is a rare neurological disorder with a sudden, temporary episode of memory loss which usually occurs in old age. The episodic loss of memory becomes normal after a stipulated time of approximately 24 hours. The precise pathology is not yet completely understood. Moreover, there is no proper neuroimaging method to assess this condition. In this study, the EEG was measured at two time points one with the occurrence of the episode (acute) and the second time point after the patient returns to the normal memory condition (follow-up). The aim of the study was to look at the pathological network involved during the acute phase and the follow up phase in these patients for the five frequency bands, namely, delta, theta, alpha, beta, and gamma. The method used for the source analyses was a beamforming approach called dynamic imaging of coherent sources in the frequency domain. The seed voxel was the lesion area taken from the anatomical MRI of each patient. The cortical and subcortical network comprised of the caudate and cerebellum in case of the delta band frequency. Two temporal sources in case of the theta band. Temporal, medial frontal, parietal, putamen, and thalamus sources were found in case of the alpha band. Prefrontal, parietal, and thalamus sources were found in case of the beta band. Temporal and thalamus in case of the gamma band frequency. All these sources were involved in the acute phase. Moreover, in the follow-up phase the motor area, in all frequency bands except gamma band, was additionally active followed by parietal and occipital regions in alpha and gamma frequencies. The differences involved in the network of sources between the two phases gives us better understanding of this neurological disorder.

[Neuroenhancement]. / Neuroenhancement.

BACKGROUND: Cognitive enhancement or neuroenhancement describes the increase in cognitive performance in humans by means of psychotropic drugs or brain stimulation methods, such as transcranial magnetic stimulation (TMS). PROBLEM: This article discusses the potential of pharmacological cognitive enhancement with some of the most common drugs. METHODS: A selective literature search was performed taking into account the most important groups of substances (i.e. caffeine, nicotine, stimulants including modafinil, and acetylcholine esterase inhibitors) for which studies on the pharmacological elevation of cognitive performance in healthy subjects are available. RESULTS: The extent of the effects that can be pharmacologically achieved is essentially genetically determined. Some of the best-characterized polymorphisms are described here. Pharmacological enhancement of cognitive performance is currently possible with all of the compounds described here and caffeine and nicotine are used by millions of people without the explicit intention of most consumers of cognitive enhancement. DISCUSSION: Clinical neuroscientists are required to share their expertise to a greater extent in the social discourse on cognitive enhancement in the future in order to influence opinion-forming and decision-making processes.

[Frontotemporal dementias]. / Frontotemporale Demenzen.

Frontotemporal dementias (FTD) account for only 5-7% of all dementia aetiologies. However, FTD is one common form of dementia in the presenile period with a symptom onset between an age of 45 and 65 years. FTD are clinically classified into a group of rare genetic variants, the behavioural variant, primary progressive aphasias and a variant including motor neuron symptoms (FTD-MNS). In recent years the pathobiological characteristics of some FTD variants was clarified, demonstrating a pathological accumulation of TAR-DNA binding protein 43 (TDP-43) as a common pathological substrate. The revised diagnostic criteria of the behavioural variant of the FTD require at least three of six clinically discriminating features (disinhibition, apathy, loss of sympathy, perseverative behaviours, hyperorality and dysexecutive neuropsychological profile). The primary progressive aphasias are classified in a nonfluent/agrammatic variant, a logopenic variant and a semantic variant according to clinical and imaging features. Movement disorders and more precisely a Parkinsonian syndrome can be part of the FTD spectrum. Some clinical features overlap the clinical diagnosis of a progressive supranuclear paralysis and the corticobasal ganglionic degeneration. A causal therapy does not exist and medical treatment is directed at the patient's key symptoms. Different agents such as serotonin reuptake inhibitors, tricyclic antidepressants, atypical neuroleptics, carbamazepine, valproate, lamotrigine and when indicated also acetylcholinesterase inhibitors are potentially helpful. All together, theses medical treatments have a low level of evidence. Non-pharmacological therapies such as physiotherapy, occupational therapy, speech therapy and disease-specific education of the patient and their relatives are important to ensure a safe residential environment and daily routine.

Deep brain stimulation of the posterior hypothalamic area in intractable short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT).

BACKGROUND: SUNCT (short-lasting unilateral neuralgiform headache with conjunctival injection and tearing) is a rare syndrome characterized by the sudden onset of excruciating unilateral periorbital pain that is accompanied by conjunctival injection and lacrimation or further autonomic signs. Similar to patients with chronic cluster headache, Leone and Lyons showed a beneficial effect of deep brain stimulation of the posterior hypothalamic region in two patients with a chronic SUNCT. CASE: Here, we present the case of a man with a chronic SUNCT responding to deep brain stimulation of the posterior hypothalamic area. CONCLUSION: This case supports the idea of a central origin of SUNCT and shows that deep brain stimulation of the hypothalamic region can be effective in the treatment of the chronic form of this rare disorder.

MR imaging findings in patients with secondary intracranial hypertension.

BACKGROUND AND PURPOSE: IH can alter the configuration of anatomic structures of the central nervous system. We determined the sensitivity and specificity of MR imaging to detect these changes in patients with secondary IH. MATERIALS AND METHODS: Patients (n = 36) with IH were prospectively investigated with MR imaging and were matched to 36 controls. MR images were evaluated for elongation and edema of the optic nerves, protrusion of the optic disc, flattening of the posterior sclera, height of the pituitary gland, and width of the optic nerve sheath. On MRV, we recorded venous sinus abnormalities and measured the luminal width of the superior ophthalmic veins. A grading score was introduced to define cranial venous outflow obstruction. RESULTS: Cranial venous outflow obstruction and ONS hydrops were the most valid signs indicating IH with a sensitivity of 94% and 92% and a specificity of 100% and 89%, respectively. Sensitivities and specificities were 56% and 97% for reduced pituitary height, 64% and 78% for flattening of the posterior sclera, 31% and 97% for widening of the superior ophthalmic veins, 33% and 100% for optic disc protrusion, 14% and 100% for optic nerve edema, and 6% and 100% for elongation of the optic nerve. At least 2 MR imaging findings could be demonstrated in each patient but in none of the controls. The number of positive MR imaging findings correlated with CSF pressure (r = 0.62, P = .01). CONCLUSIONS: The combination of cranial and orbital MR imaging and MRV can be highly sensitive and specific in the diagnosis of patients with IH.

Contrast-enhanced magnetic resonance angiography in stroke diagnostics: additional information compared with time-of-flight magnetic resonance angiography?

PURPOSE: The aim of this study was a comparison of the diagnostic value of time-of-flight magnetic resonance angiography (TOF-MRA) and contrast-enhanced (CE) MRA in the setting of acute stroke MRI. The hypothesis was that CE-MRA has at least the same diagnostic value as the commonly used TOF-MRA. MATERIALS AND METHODS: A total of 66 stroke patients underwent MRI up to 24 h after symptom onset and again after 3­6 days. Primary slices and maximum intensity projections (MIP) of both techniques were evaluated separately and in combination by two readers in consensus. The quality of imaging and degree of vascular pathologies were evaluated. RESULTS: Out of 109 examinations 105 could be evaluated. There were no significant differences in imaging quality in normal vascular segments. For arterial segments distal to an occlusion CE-MRA allowed better visualization of vessels than TOF-MRA. A combined evaluation of both techniques allowed a significantly better assessment than evaluation of images by one technique alone. In contrast to TOF-MRA, CE-MRA included extracranial segments. CONCLUSION: CE-MRA and TOF-MRA do not differ regarding the evaluation of normal intracranial vessels. CE-MRA provides the advantage of good visualization of vessels distal to occluded segments. Furthermore CE-MRA allows visualization of extracranial vessels and faster image acquisition. TOF-MRA can be equivalently used if the administration of contrast agents is not possible.

Distribution of 5-HT(1B), 5-HT(1D) and 5-HT(1F) receptor expression in rat trigeminal and dorsal root ganglia neurons: relevance to the selective anti-migraine effect of triptans.

Triptans, acting as serotonin, 5-HT(1B/1D/1F), receptor agonists, provide an effective and established treatment option in migraine and cluster headache. Clinical observations suggest a relatively specific effect of these compounds on primary headache disorders, but not in other pain syndromes. The mechanism of this specificity, however, is not well understood. Hence, we systematically studied primary sensory ganglia in rat to determine if the peripheral distribution of 5HT(1B/1D/1F) receptors showed any anatomical difference that would account for the specificity of clinical effect. Rat primary afferent and sensory ganglia neurons--trigeminal ganglia (Vg), and dorsal root ganglia (DRG): C(2), C(5), T(5), L(5)--were examined using paraffin-embedded, slide-bound tissue sections reacted with specific primary antibodies for rat 5-HT(1B, 1D) and (1F) receptors in a peroxidase-based immunohistochemical method. Immunoreactivity specific for all three serotonergic receptor subtypes was demonstrated in the five peripheral nervous system regions examined and quantitated. There was a good agreement for 5-HT(1B) and 5-HT(1D) receptors to that previously demonstrated in Vg and DRG L(5), while this was the first characterisation for 5-HT(1F) receptor in any of the five regions, as well as for 5-HT(1B) and 5HT(1D) receptors in DRG C(2), C(5) and T(5). In summary, all three 5-HT receptors are equally represented in Vg and the DRGs examined. We conclude that the triptans are theoretically able to bind to receptors at each level of the peripheral neuraxis without any apparent anatomical preference for the head.

Focal lesions of human hippocampal CA1 neurons in transient global amnesia impair place memory.

A critical role in place learning has been attributed to place cells within the cornu ammonis 1 (CA1) sector of the hippocampus in rodents. The role of CA1 cells in the human hippocampus with regard to place learning remains elusive. Using a virtual Morris water maze, we investigated patients with acute transient global amnesia (TGA), a rare self-limiting dysfunction of the hippocampal system. Fourteen individuals with selective and focal lesions in the CA1 sector of the hippocampus showed a profound impairment in place learning. The size of the lesions and the duration of the TGA correlated with the deficit in the performance.

MR imaging of the optic nerve sheath in patients with craniospinal hypotension.

BACKGROUND AND PURPOSE: Craniospinal hyper- or hypotension leads to morphologic changes in certain intracranial structures. We tested the hypothesis that the amount of CSF in the ONS visible in MR imaging is reduced in patients with CSH. MATERIALS AND METHODS: Nineteen patients with CSH were prospectively studied. Three readers assessed the width of the peri-optical CSF rim at 4 different anatomic positions by using coronal STIR sequences from a 3T MR imaging scanner. The height of the pituitary gland was also measured. Results were compared with normal values obtained with the same imaging technique. Qualitative signs of CSH also recorded were engorgement of venous sinuses, dural enhancement, subdural effusion, narrow ventricles, and sagging brain. RESULTS: CSF signal intensity surrounding the optic nerves was diminished in at least 2 of the 4 positions used for measurements so that decreased diameters of the ONSs were observed in all patients (sensitivity, 100%; specificity, 97%). The height of the pituitary gland was above normal limits in 12 of 19 patients (sensitivity, 63%; specificity, 97%). Frequencies of qualitative signs of CSH varied from 32% to 81%. CONCLUSIONS: The ISSON in patients with CSH is partially or fully collapsed due to reduced CSF content. In comparison with other anatomic markers, this sign showed the highest sensitivity for the diagnosis of patients with CSH in this study.

Failure of deep brain stimulation of the posterior inferior hypothalamus in chronic cluster headache - report of two cases and review of the literature.

OBJECTIVE: Deep brain stimulation (DBS) has become a standard procedure for movement disorders such as Parkinson's disease, essential tremor or dystonia. Recently, deep brain stimulation of the posterior hypothalamus has been shown to be effective in the treatment of drug-resistant chronic cluster headache. METHODS: DBS of the posterior inferior hypothalamus was performed on two patients with chronic cluster headaches, one 55-year-old man with medically intractable chronic cluster headache since 1996, and one 31-year-old woman with a chronic form since 2002. Both patients showed continuous worsening headaches in the last years despite high dose medical treatment. The patients fulfilled the published criteria for DBS in chronic cluster headaches. Electrodes were implanted stereotactically in the ipsilateral posterior hypothalamus according to the published coordinates (2 mm lateral, 3 mm posterior, 5 mm inferior) referenced to the mid-AC-PC line. RESULTS: The intra- and postoperative course was uneventful and postoperative MRI control documented regular position of the DBS electrodes. The current stimulation parameters were at 12 months postoperatively 0 neg., G pos.; 5.5 V; 60 micros; 180 Hz (Case 1) and 0 neg., G pos.; 3.0 V; 60 micros; 185 Hz, at 3 months postoperatively (Case 2). Surgery- or stimulation-related side effects were not observed. Both patients showed initial pain reduction in the first days whereas 12 respectively 3 month follow-up did not show a significant reduction in attack frequency or intensity. CONCLUSION: Deep brain stimulation of the posterior inferior hypothalamus is an experimental procedure and should be restricted to selected therapy-refractory patients and should be performed in centers experienced in patient selection and performance of DBS as well as postoperative pain treatment. A prospective multi-centre study is necessary to evaluate its effectiveness.

Focal MR spectroscopy of hippocampal CA-1 lesions in transient global amnesia.

OBJECTIVE: The pathomechanisms of transient global amnesia (TGA) remain enigmatic. Focal MR signal diffusion changes in the CA-1 sector of the hippocampus have been described in transient global amnesia, but the pathophysiologic correlate of these lesions is unknown. METHODS: We studied the metabolic spectra of diffusion lesions in the CA-1 sector hippocampus of seven patients with TGA using MR spectroscopy (MRS) between 24 and 72 hours after onset and 2 to 5 months later. The amnestic deficit was studied using a neuropsychometric test battery. RESULTS: Four out of seven patients with an acute TGA showed a diffusion lesion with a corresponding T2 lesion in the CA-1 sector of the hippocampus. Selective hippocampal MRS of diffusion lesions showed a lactate peak in three of four patients, but not in patients without a diffusion lesion. The NAA/creatine ratio was normal. CONCLUSION: Lactate as a marker of anaerobic glycolysis indicates acute metabolic stress of CA-1 neurons in TGA whereas long-term neuronal metabolic changes are not found. This implies that the acute effect on hippocampal CA-1 neurons is the functional correlate of a transient global amnesia reflecting a transient perturbation of memory relevant circuits in the hippocampus.

Hypothalamic deep brain stimulation for cluster headache: experience from a new multicase series.

Deep brain stimulation (DBS) of the posterior hypothalamus was found to be effective in the treatment of drug-resistant chronic cluster headache. We report the results of a multicentre case series of six patients with chronic cluster headache in whom a DBS in the posterior hypothalamus was performed. Electrodes were implanted stereotactically in the ipsilateral posterior hypothalamus according to published coordinates 2 mm lateral, 3 mm posterior and 5 mm inferior referenced to the mid-AC-PC line. Microelectrode recordings at the target revealed single unit activity with a mean discharge rate of 17 Hz (range 13-35 Hz, n = 4). Out of six patients, four showed a profound decrease of their attack frequency and pain intensity on the visual analogue scale during the first 6 months. Of these, one patient was attack free for 6 months under neurostimulation before returning to the baseline which led to abortion of the DBS. Two patients had experienced only a marginal, non-significant decrease within the first weeks under neurostimulation before returning to their former attack frequency. After a mean follow-up of 17 months, three patients are almost completely attack free, whereas three patients can be considered as treatment failures. The stimulation was well tolerated and stimulation-related side-effects were not observed on long term. DBS of the posterior inferior hypothalamus is an effective therapeutic option in a subset of patients. Future controlled multicentre trials will need to confirm this open-label experience and should help to better define predictive factors for non-responders.