Free-water metrics in medial temporal lobe white matter tract projections relate to longitudinal cognitive decline.

Although hippocampal volume has served as a long-standing predictor of cognitive decline, diffusion magnetic resonance imaging studies of white matter have shown similar relationships. Still, it remains unclear if gray matter and white matter interact to predict cognitive impairment and longitudinal decline. Here, we investigate whether free-water (FW) and FW-corrected fractional anisotropy (FAT) within medial temporal lobe white matter tracts provides meaningful contribution to cognition and cognitive decline beyond hippocampal volume. Using data from the Vanderbilt Memory & Aging Project (n = 319), we found that FW was associated with baseline memory and executive function beyond that of hippocampal volume and other comorbidities. Longitudinal analyses demonstrated significant interactions of hippocampal volume and inferior longitudinal fasciculus (p = 0.043) and cingulum bundle (p = 0.025) FAT on memory decline and with fornix FAT (p = 0.025) on decline in executive function. Results suggest that FW metrics of white matter have a unique role in cognitive decline and should be included in theoretical models of aging, cerebrovascular disease, and Alzheimer's disease.

Gradient subthalamic neurodegeneration and tau pathology in the hypoglossal nucleus as essential pathological markers of progressive supranuclear palsy - Richardson syndrome.

Progressive supranuclear palsy - Richardson syndrome (PSP-RS) was first described in 1964 by Steele et al. Tau pathology has not been reported in the hypoglossal nuclei of PSP-RS patients, whereas Steele et al. described gliosis with no remarkable neuronal losses in the hypoglossal nucleus. This study aimed to investigate the distribution and degree of tau pathology-associated neurodegeneration, with an emphasis on the hypoglossal nucleus, in patients with PSP-RS. Six clinicopathologically proven PSP-RS cases were included in this study. All patients were clinicopathologically and immunohistochemically re-evaluated. This study confirmed the following neuropathological characteristics of PSP-RS: (1) neurodegeneration usually affects the striatonigral system and cerebellar dentate nucleus; (2) the cerebellar afferent system in PSP-RS is affected by absent-to-mild neurodegeneration; and (3) the extent of tau distribution throughout the central nervous system is greater than the extent of neurodegeneration. Furthermore, we found that subthalamic neurodegeneration was more prominent in the ventromedial region than in the dorsolateral region. Nevertheless, the tau pathology showed no remarkable differences between these two sites. Interestingly, the tau pathology was frequently observed in the hypoglossal nuclei of PSP-RS patients. Gradient neurodegeneration of the subthalamus and tau pathology in the hypoglossal nucleus could be regarded as essential pathological features of PSP-RS.

Verbal Memory Decline following DBS for Parkinson's Disease: Structural Volumetric MRI Relationships.

BACKGROUND: Parkinson's disease is a chronic degenerative movement disorder. The mainstay of treatment is medical. In certain patients Deep Brain Stimulation (DBS) may be offered. However, DBS has been associated with post-operative neuropsychology changes, especially in verbal memory. OBJECTIVES: Firstly, to determine if pre-surgical thalamic and hippocampal volumes were related to verbal memory changes following DBS. Secondly, to determine if clinical factors such as age, duration of symptoms or motor severity (UPDRS Part III score) were related to verbal memory changes. METHODS: A consecutive group of 40 patients undergoing bilateral Subthalamic Nucleus (STN)-DBS for PD were selected. Brain MRI data was acquired, pre-processed and structural volumetric data was extracted using FSL. Verbal memory test scores for pre- and post-STN-DBS surgery were recorded. Linear regression was used to investigate the relationship between score change and structural volumetric data. RESULTS: A significant relationship was demonstrated between change in List Learning test score and thalamic (left, p = 0.02) and hippocampal (left, p = 0.02 and right p = 0.03) volumes. Duration of symptoms was also associated with List Learning score change (p = 0.02 to 0.03). CONCLUSION: Verbal memory score changes appear to have a relationship to pre-surgical MRI structural volumetric data. The findings of this study provide a basis for further research into the use of pre-surgical MRI to counsel PD patients regarding post-surgical verbal memory changes.

White matter alterations in patients with MRI-negative temporal lobe epilepsy and their asymptomatic siblings.

OBJECTIVE: The identification of "endophenotypes"-measurable variations along the pathways between genes and distal disease state-may help deconstruct focal epilepsies into more sensitive phenomena and improve future efforts to map the genetic underpinnings of the disorder. In this study, we set out to determine if diffusion tensor imaging (DTI)-inferred white matter (WM) alterations represent a suitable structural endophenotype for focal epilepsy. METHODS: We recruited 25 patients with sporadic mesial temporal lobe epilepsy (MTLE) with normal magnetic resonance imaging (MRI) findings, 25 of their gender-matched, asymptomatic siblings, and 60 control subjects. Whole-brain, voxelwise statistics were conducted to identify regions of microstructural degeneration in patients with MTLE and/or their asymptomatic siblings. WM tracts exhibiting evidence of microstructural disruption were then reconstructed using deterministic tractography. Diffusion metrics including fractional anisotropy (FA) and mean diffusivity (MD) were compared across groups using a series of one-way multivariate analyses of covariance (MANCOVAs). RESULTS: Voxelwise statistics revealed significant FA reductions in the corpus callosum (CC), bilateral superior longitudinal fasciculi (SLF), bilateral inferior longitudinal fasciculi (ILF), and left corticospinal tract (CST) in MTLE patients only. MD increases were observed in MTLE patients and their asymptomatic siblings in the left SLF and left CST. Deterministic tractography supported the voxelwise results, revealing significant FA alterations in the left SLF and CST in patients only and significant MD alterations in MTLE patients and their unaffected siblings. The diffusion scalars of MTLE patients and their asymptomatic siblings were highly correlated in the SLF and CST ipsilateral to patients' sides of seizure onset. SIGNIFICANCE: These findings confirm the presence of microstructural WM alterations in patients with MRI-negative MTLE and provide preliminary support for a diffusion-based endophenotype in the disorder. Further studies of narrow-sense heritability in larger cohorts of first-degree relatives of MTLE patients are required to confirm these results.

Optimizing Prelemniscal Radiations as a Target for Motor Symptoms in Parkinson's Disease Treatment.

OBJECTIVE: To better define prelemniscal radiations (Raprl) as a target for the control of tremor and rigidity in Parkinson's disease (PD). METHODS: A total of 36 deep brain stimulation (DBS) electrodes were stereotactically implanted in Raprl contralateral to the extremities to be treated. Effects on symptoms were evaluated using UPDRS-III before and after DBS, and significance was determined using the Wilcoxon test. The location of DBS contacts in cases with optimum versus suboptimum results was evaluated using Student's t test and percentage improvement correlated through a bivariable Pearson test. The power and percentage of spike components for microelectrode recordings were statistically compared between the target point and structures located above and below. RESULTS: Raprl-DBS improved tremor and rigidity (p < 0.01). The potency of microelectrode recordings indicated that the target was formed by fibers. There was no correlation between demographic characteristics and clinical outcome, and there were no significant differences in stereotactic placement between cases with optimum and suboptimum results. Tremor and rigidity were selectively improved in cases with suboptimum results. CONCLUSION: Raprl-DBS is an effective treatment for the motor symptoms of PD. Selective improvement of symptoms suggests that the target has different fiber components related to either tremor or rigidity, and variations in improvement between cases may derive from individual variations of the location of these fibers.

Adding insult to injury: childhood and adolescent risk factors for psychosis predict lower fractional anisotropy in the superior longitudinal fasciculus in healthy adults.

Although epidemiological studies provide strong support for demographic and environmental risk factors in psychotic disorders, few data examine how these risk factors relate to the putative aberrant neurodevelopment associated with illness. The present study examined how the accumulation of risk factors including low IQ, low parental socioeconomic status (SES), history of adolescent cannabis use and childhood trauma, and high levels of subclinical psychotic-like experiences (PLEs) contributed to aberrant neurodevelopmental outcomes in 112 otherwise healthy adults recruited from the community. Participants were studied with diffusion tensor imaging (DTI), and voxel-wise statistical analysis of fractional anisotropy (FA) using tract-based spatial statistics (TBSS) was used to examine the relation between cumulative risk (CR) for psychosis and white matter (WM) integrity across the whole brain. Analyses revealed that higher CR was significantly associated with lower FA in a cluster in the left superior longitudinal fasciculus (SLF). These results suggest that risk factors previously associated with psychotic disorders are associated with WM integrity even in otherwise healthy adults and may provide insight into how previously identified risk factors contribute to the structural brain abnormalities associated with psychotic illness. Prospective longitudinal studies examining the effect of risk factors on the developmental trajectory of brain WM are warranted.

The Arcuate Fasciculus in auditory-verbal hallucinations: a meta-analysis of diffusion-tensor-imaging studies.

Auditory-verbal hallucinations (AVHs) are associated with an impaired connectivity of large-scale networks. To examine the relationship between white-matter integrity and AVHs, we conducted a meta-analysis of diffusion-tensor-imaging studies that compared patients with schizophrenia and AVHs with matched healthy controls (HCs). Five studies were retained gathering 256 DTI data points, divided into AVHs (n=106) and HCs (n=150). The meta-analysis demonstrated a reduced fractional anisotropy in the left Arcuate Fasciculus (AF) of hallucinators (hg= -0.42; CI[-0.69,-0.16]; p<10(-3)). The current meta-analysis confirmed disruptions of white matter integrity in the left AF bundle of schizophrenia patients with AVHs.

[Case of wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome with cerebellar ataxia and facial dysesthesia].

We report an 85-year-old man presenting with wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome with cerebellar ataxia and facial dysesthesia. He experienced an abrupt onset of double vision and exotropia of the right eye with unsteady gait and dysesthesia around upper lip. He was admitted to our hospital ten days after the onset of the double vision. On admission, he presented with WEBINO, left limb ataxia, and dysesthesia around upper lip on the right side. His exotropia was prominent on the right side. Diffusion weighted images of MRI revealed a high intensity lesion in the paramedian pontine tegmentum involving bilateral medial longitudinal fasciculus (MLF), consistent with acute ischemic lesion. Four months after the onset, the WEBINO persisted, without cerebellar ataxia and facial dysesthesia. Putative lesions of the WEBINO, cerebellar ataxia and facial dysesthesia were bilateral MLF, left superior cerebellar peduncle and trigeminothalamic tract, respectively, which were broader than the MRI lesion. Neurological examination is critical for evaluation of accurate ischemic area.

Possible mechanisms involved in subthalamotomy-induced dyskinesia in patients with Parkinson's disease.

BACKGROUND/AIMS: Operation-induced dyskinesia (OID) occurs in approximately 10% of patients submitted to subthalamotomy. The goal of the authors was to determine the possible causes of this feared complication. METHODS: The 54 patients who underwent unilateral subthalamotomy were divided into two groups: the OID group (OIDG), composed of 6 patients who developed dyskinesia following the operation, and the control group (CG), consisting of 48 patients who did not present this complication. The two groups were compared regarding age; sex; presence of levodopa-induced dyskinesia (LID) and/or stimulation-induced dyskinesia (SID); side of the operation; territories of the subthalamic nucleus (STN) involved by the lesion, and degree of lesion extension towards the zona incerta (ZI). RESULTS: The lesion involved the dorsolateral territory of the STN and was almost completely restricted to this nucleus in all patients of the OIDG, while it spread to the ZI in all but 1 patient of the CG. SID was significantly (p < 0.05) more frequent in the OIDG. There was also a strong trend favoring LID (p = 0.055). CONCLUSIONS: Damage to the dorsolateral territory of the STN and sparing of the ZI seem to be essential for the development of OID. SID and, to a lesser extent, LID are apparently significant risk factors for the development of this complication.

Antinociceptive effect of stimulating the zona incerta with glutamate in rats.

The zona incerta (ZI) is a subthalamic nucleus connected to several structures, some of them known to be involved with antinociception. The ZI itself may be involved with both antinociception and nociception. The antinociceptive effects of stimulating the ZI with glutamate using the rat tail-flick test and a rat model of incision pain were examined. The effects of intraperitoneal antagonists of acetylcholine, noradrenaline, serotonin, dopamine, or opioids on glutamate-induced antinociception from the ZI in the tail-flick test were also evaluated. The injection of glutamate (7 µg/0.25 µl) into the ZI increased tail-flick latency and inhibited post-incision pain, but did not change the animal performance in a Rota-rod test. The injection of glutamate into sites near the ZI was non effective. The glutamate-induced antinociception from the ZI did not occur in animals with bilateral lesion of the dorsolateral funiculus, or in rats treated intraperitoneally with naloxone (1 and 2 m/kg), methysergide (1 and 2 m/kg) or phenoxybenzamine (2 m/kg), but remained unchanged in rats treated with atropine, mecamylamine, or haloperidol (all given at doses of 1 and 2 m/kg). We conclude that the antinociceptive effect evoked from the ZI is not due to a reduced motor performance, is likely to result from the activation of a pain-inhibitory mechanism that descends to the spinal cord via the dorsolateral funiculus, and involves at least opioid, serotonergic and α-adrenergic mechanisms. This profile resembles the reported effects of these antagonists on the antinociception caused by stimulating the periaqueductal gray or the pedunculopontine tegmental nucleus.

Photobiomodulation enhances nigral dopaminergic cell survival in a chronic MPTP mouse model of Parkinson's disease.

We have shown previously that photobiomodulation or near-infrared light (NIr) treatment protects dopaminergic cells of the substantia nigra pars compacta (SNc) in an acute MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease (PD). In this study, we tested the protective and rescue action of NIr treatment in a chronic MPTP model, developed to resemble more closely the slow progressive degeneration in PD patients. We examined three regions of dopaminergic cells, the SNc, periaqueductal grey matter (PaG) and zona incerta-hypothalamus (ZI-Hyp). BALB/c mice had MPTP or saline injections over five weeks, followed by a three-week survival. NIr treatment was applied either at the same time as (simultaneous series) or after (post-treatment series) the MPTP insult. There were four groups within each series; Saline, Saline-NIr, MPTP and MPTP-NIr. Brains were processed for tyrosine hydroxylase (TH) immunochemistry and cell number was analysed using the optical fractionator method. In the SNc, there was a significant reduction (≈ 45%) in TH(+) cell number in the MPTP groups compared to the saline controls of both series. In the MPTP-NIr groups of both series, TH(+) cell number was significantly higher (≈ 25%) than in the MPTP groups, but lower than in the saline controls (≈ 20%). By contrast in the PaG and ZI-Hyp, there were no significant differences in TH(+) cell number between the MPTP an MPTP-NIr groups of either series. In summary, exposure to NIr either at the same time or well after chronic MPTP insult saved many SNc dopaminergic cells from degeneration.

Effects of zona incerta lesions on striatal neurochemistry and behavioral asymmetry in 6-hydroxydopamine-lesioned rats.

Analysis of optimal sites for neurosurgical interventions in patients with Parkinson's disease (PD) suggests that significant clinical benefits may be achieved by involvement of the zona incerta (ZI). Unilateral electrolytic ZI lesions were made in intact and ipsilaterally 6-hydroxydopamine (6OHDA)-lesioned rats. Extracellular levels of glutamate, dopamine, and its metabolites in the ipsilateral striatum of awake rats were measured by using microdialysis, and tests of behavioral asymmetry were performed. In intact rats, ZI lesions had no effect on striatal extracellular glutamate or absolute levels of dopamine or metabolites, but dopamine metabolism decreased. After ZI lesions, contralateral forepaw use decreased in the forepaw adjusting steps test, but there was no change in response to vibrissa stimulation or cylinder exploration. There was no development of rotational asymmetry with amphetamine. In 6OHDA-lesioned rats, striatal extracellular glutamate levels were elevated compared with controls. ZI lesions reduced the increased levels of glutamate back to normal values. ZI lesions reduced dopamine and homovanillic acid levels and showed a trend toward a decrease in dopamine metabolism. 6OHDA-lesioned rats demonstrated the expected asymmetry of motor behaviors. After ZI lesions, ipsilateral turns following amphetamine injection were reduced, and there was a trend toward improved symmetry of forepaw use as determined with the forepaw adjusting steps test. There was no change in forepaw use with vibrissa stimulation or cylinder exploration. These data indicate that lesions of the ZI can affect striatal neurochemistry and motor behavioral asymmetry and suggest potential mechanisms by which ZI lesions may improve symptoms in PD.

Zona incerta: a role in central pain.

Central pain syndrome (CPS) is a debilitating condition that affects a large number of patients with a primary lesion or dysfunction in the CNS. Despite its discovery over a century ago, the pathophysiological processes underlying the development and maintenance of CPS are poorly understood. We recently demonstrated that activity in the posterior thalamus (PO) is tightly regulated by inhibitory inputs from zona incerta (ZI). Here we test the hypothesis that CPS is associated with abnormal inhibitory regulation of PO by ZI. We recorded single units from ZI and PO in animals with CPS resulting from spinal cord lesions. Consistent with our hypothesis, the spontaneous firing rate and somatosensory evoked responses of ZI neurons were lower in lesioned animals compared with sham-operated controls. In PO, neurons recorded from lesioned rats exhibited significantly higher spontaneous firing rates and greater responses to noxious and innocuous stimuli applied to the hindpaw and to the face. These changes were not associated with increased afferent drive from the spinal trigeminal nucleus or changes in the ventroposterior thalamus. Thus CPS can result from suppressed inputs from the inhibitory nucleus zona incerta to the posterior thalamus.

Assessing the microlesion effect of subthalamic deep brain stimulation surgery with FDG PET.

OBJECT: The authors investigated whether the insertion of deep brain stimulation electrodes into the subthalamic nucleus can alter regional brain metabolism in the absence of stimulation. METHODS: Six patients with Parkinson disease (PD) underwent preoperative FDG PET scanning, and again after STN electrode implantation with stimulation turned off. RESULTS: Compared with baseline values, glucose utilization was reduced in the postoperative off-stimulation scans in the putamen/globus pallidus and in the ventral thalamus (p < 0.01), and there was increased metabolism in the sensorimotor cortex and cerebellum (p < 0.005). The expression of a specific PD-related spatial covariance pattern measured in the FDG PET data did not change after electrode implantation (p = 0.36), nor was there a significant change in clinical motor ratings (p = 0.44). Differences in PD-related spatial covariance pattern expression among the patients after electrode implantation did, however, correlate with the number of microelectrode recording trajectories placed during surgery (r = -0.82, p < 0.05). CONCLUSIONS: These findings suggest that electrode implantation can impart a microlesion effect on regional brain function. Nonetheless, these local changes did not cross the threshold of network modulation needed to achieve clinical benefit.

MTHFR homozygous mutation and additional risk factors for cerebral infarction in a large Italian family.

Several cases with cerebral infarctions associated with the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) have been reported. Given the large number of asymptomatic individuals with the MTHFR mutation, additional risk factors for cerebral infarction should be considered. This study describes a large family with the MTHFR mutation and a combination of heterozygous factor V Leiden mutations and different additional exogenous and endogenous thrombogenic risk factors. Psychomotor retardation and a left fronto-insular infarct associated with the MTHFR mutation together with diminished factor VII and low level of protein C was documented in the first patient. In the second patient, generalized epilepsy and a malacic area in the right nucleus lenticularis was associated with the MTHFR mutation and a low level of protein C. In the third patient, right hemiparesis and a left fronto-temporal porencephalic cyst were documented, together with the MTHFR mutation and hyperhomocysteinemia. An extensive search of additional circumstantial and genetic thrombogenic risk factors should be useful for prophylaxis and prognosis of infants with cerebral infarctions associated with the MTHFR mutation and of their related family members.

Unawareness of "illnesses": a case of right-sided hemiballism.

The Authors describe a non-demented patient who, after a left subthalamic haemorrhage causing hemiballism, was completely unaware of both neurological (i.e., dyskinesias) and non-neurological (i.e., cough) symptoms occurring after the stroke. In contrast, he was perfectly able to acknowledge pathological conditions affecting him before the brain damage. Neuropsychological assessment showed no cognitive defects, but revealed the presence of frontal behaviours (e.g., perseverations and utilization behaviours). This unusual clinical picture was ascribed to damage of frontal-subcortical circuits involved in conscious representation of current bodily states.

Stimulation of the caudal zona incerta is superior to stimulation of the subthalamic nucleus in improving contralateral parkinsonism.

Deep brain stimulation (DBS) has an increasing role in the treatment of idiopathic Parkinson's disease. Although, the subthalamic nucleus (STN) is the commonly chosen target, a number of groups have reported that the most effective contact lies dorsal/dorsomedial to the STN (region of the pallidofugal fibres and the rostral zona incerta) or at the junction between the dorsal border of the STN and the latter. We analysed our outcome data from Parkinson's disease patients treated with DBS between April 2002 and June 2004. During this period we moved our target from the STN to the region dorsomedial/medial to it and subsequently targeted the caudal part of the zona incerta nucleus (cZI). We present a comparison of the motor outcomes between these three groups of patients with optimal contacts within the STN (group 1), dorsomedial/medial to the STN (group 2) and in the cZI nucleus (group 3). Thirty-five patients with Parkinson's disease underwent MRI directed implantation of 64 DBS leads into the STN (17), dorsomedial/medial to STN (20) and cZI (27). The primary outcome measure was the contralateral Unified Parkinson's Disease Rating Scale (UPDRS) motor score (off medication/off stimulation versus off medication/on stimulation) measured at follow-up (median time 6 months). The secondary outcome measures were the UPDRS III subscores of tremor, bradykinesia and rigidity. Dyskinesia score, L-dopa medication reduction and stimulation parameters were also recorded. The mean adjusted contralateral UPDRS III score with cZI stimulation was 3.1 (76% reduction) compared to 4.9 (61% reduction) in group 2 and 5.7 (55% reduction) in the STN (P-value for trend <0.001). There was a 93% improvement in tremor with cZI stimulation versus 86% in group 2 versus 61% in group 1 (P-value = 0.01). Adjusted 'off-on' rigidity scores were 1.0 for the cZI group (76% reduction), 2.0 for group 2 (52% reduction) and 2.1 for group 1 (50% reduction) (P-value for trend = 0.002). Bradykinesia was more markedly improved in the cZI group (65%) compared to group 2 (56%) or STN group (59%) (P-value for trend = 0.17). There were no statistically significant differences in the dyskinesia scores, L-dopa medication reduction and stimulation parameters between the three groups. Stimulation related complications were seen in some group 2 patients. High frequency stimulation of the cZI results in greater improvement in contralateral motor scores in Parkinson's disease patients than stimulation of the STN. We discuss the implications of this finding and the potential role played by the ZI in Parkinson's disease.

[Subthalamic deep brain stimulation for severe idiopathic Parkinson's disease. Location study of the effective contacts]. / Stimulation sous-thalamique dans la maladie de Parkinson severe. étude de la localisation des contacts effectifs.

The subthalamic nucleus (STN) is the main target of deep brain stimulation (DBS) treatment for severe idiopathic Parkinson's disease. But there is still no clear information on the location of the effective contacts (used during the chronic phase of stimulation). Our aim was to assess the anatomical structures of the subthalamic area (STA) involved during chronic DBS. Ten patients successfully treated were included. The surgical procedure was based on direct STN targeting (stereotactic MRI based) pondered by the acute effects of intraoperative stimulation. We used a formaldehyde-fixed human specimen to compare by matching MRI images obtained at 1.5 Tesla (performed in clinical stereotactic conditions) and at very high field at 4.7 Tesla. This allowed accurate analysis of the anatomy of the STA and retrospective precision of the location of the center of effective contacts which were located within the STN in 4 patients, at the interface between the STN and the ZI and/or FF in 13, at the interface between ZI and FF in 2 and between the STN and the substantia nigra in one. These results were consistent with the literature, revealing the implication of neighboring structures, especially the zona incerta and Forel's Field, in the clinical benefit.

Conjugate eye deviation due to traumatic striatal-subthalamic lesion.

We report the case of a 22-year-old man after severe cranial trauma, who was noted to have conjugate eye deviation (CED) to the left. A magnetic resonance imaging (MRI) scan demonstrated a lesion in the left (ipsilateral) striatal-subthalamic region. The involvement of supranuclear fibres from the left frontal eye field (FEF) traveling to the right parapontine reticular formation (PPRF) could explain this clinical finding. Alternatively, involvement of deep brain nuclei, such as the striatum and the subthalamic nucleus, could be responsible for this phenomenon. This neurological presentation is unusual after severe cranial trauma.