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ObjectiveHippocampal volume is a sensitive marker of neurodegeneration and a well-established predictor of age-related cognitive impairment. Recently, free-water (FW) magnetic resonance imaging (MRI) has shown associations with pathology in Alzheimer’s disease (AD), but it is still unclear whether these metrics are associated with measures of cognitive impairment. Here, we investigate whether FW and FW-corrected fractional anisotropy (FAT) within medial temporal lobe white matter tracts (cingulum, fornix, uncinate fasciculus, inferior longitudinal fasciculus, and tapetum) provides meaningful contribution to cognition and cognitive decline beyond hippocampal volume.Participants and MethodsVanderbilt Memory & Aging Project participants (n=319, 73±7 years, 59% male) with normal cognition and mild cognitive impairment (40% of cohort) underwent baseline brain MRI, including structural MRI to quantify hippocampal volume, diffusion MRI to quantify medial temporal lobe white matter tract FW and FAT, and longitudinal neuropsychological assessment with a mean follow-up of 3.5 years. Linear regressions were conducted to determine how hippocampal volume and white matter tract FW and FAT interact with baseline memory and executive function performances. Competitive model analyses determined the unique variance provided by white matter tract FW and FAT beyond that of hippocampal volume and other comorbidities. Linear mixed-effects models were conducted to determine how baseline hippocampal volume and white matter tract FW and FAT interact to explain longitudinal change in memory and executive function performances.ResultsFW in the inferior longitudinal fasciculus, tapetum, uncinate fasciculus, and cingulum were robustly associated with baseline memory and executive function. Further, competitive model analysis showed that tract FW contributed unique variance beyond other comorbidities and hippocampal volume for memory (ΔRadj2 range: 0.82-2.00%) and executive function (ΔRadj2 range: 0.88-1.87%). Longitudinal analyses demonstrated significant interactions of hippocampal volume and FAT in the inferior longitudinal fasciculus (p=0.02), tapetum (p=0.02), uncinate fasciculus (p=0.02), and cingulum (p=0.002) with decline in memory. For decline in executive function, we found significant interactions of hippocampal volume and FAT in inferior longitudinal fasciculus (p=0.03), tapetum (p=0.02), uncinate fasciculus (p=0.02), and fornix (p=0.02), as well as cingulum (p=0.02) and fornix (p=0.02) FW.ConclusionsOur results highlight novel associations between FW and FAT measures of medial temporal lobe tract microstructure and cognitive performance such that individuals with smaller hippocampal volumes and lower tract microstructure experience greater cognitive decline. These results suggest that white matter has a unique role in cognitive decline and, therefore, could be used to provide better disease staging, allowing for more precise disease monitoring in AD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with social communication deficits and restricted/repetitive behaviors and is characterized by large-scale atypical subcortical-cortical connectivity, including impaired resting-state functional connectivity between thalamic and sensory regions. Previous studies have typically focused on the abnormal static connectivity in ASD and overlooked potential valuable dynamic patterns in brain connectivity. However, resting-state brain connectivity is indeed highly dynamic, and abnormalities in dynamic brain connectivity have been widely identified in psychiatric disorders. In this study, we investigated the dynamic functional network connectivity (dFNC) between 51 intrinsic connectivity networks in 170 individuals with ASD and 195 age-matched typically developing (TD) controls using independent component analysis and a sliding window approach. A hard clustering state analysis and a fuzzy meta-state analysis were conducted respectively, for the exploration of local and global aberrant dynamic connectivity patterns in ASD. We examined the group difference in dFNC between thalamic and sensory networks in each functional state and group differences in four high-dimensional dynamic measures. The results showed that compared with TD controls, individuals with ASD show an increase in transient connectivity between hypothalamus/subthalamus and some sensory networks (right postcentral gyrus, bi paracentral lobule, and lingual gyrus) in certain functional states, and diminished global meta-state dynamics of the whole-brain functional network. In addition, these atypical dynamic patterns are significantly associated with autistic symptoms indexed by the Autism Diagnostic Observation Schedule. These converging results support and extend previous observations regarding hyperconnectivity between thalamic and sensory regions and stable whole-brain functional configuration in ASD. Dynamic brain connectivity may serve as a potential biomarker of ASD and further investigation of these dynamic patterns might help to advance our understanding of behavioral differences in this complex neurodevelopmental disorder.

Introduction Previous studies have reported improvement of impulse control disorders (ICDs) after subthalamic nucleus (STN) deep brain stimulation (DBS) as well as some de novo ICDs. However, it is not clear how STN DBS changes ICDs in the long-term. Methods materials Eighty-nine patients with Parkinson's disease (PD) who had received a bilateral STN DBS from 2005 to 2009 and were included in our previous study were followed for 7 years with the modified Minnesota Impulsive Disorders Interview (mMIDI). Their mMIDI scores, medication, and frontal function tests measured preoperatively and at 1 and 7 years postoperatively were compared. Results A total of 61 patients were analyzed after excluding 10 and 18 patients due to death and lost to follow-up, respectively. The numbers of the patients with an ICD at each point were 8, 10, and 7, respectively. All preoperative ICDs disappeared after DBS. De novo ICDs within 1 year after DBS disappeared except for 1 patient. Six of the seven patients, who reported ICDs 7 years after the DBS developed that ICD between 1 and 7 years. Their total levodopa equivalent daily dose (LEDD) and dopamine agonist dose were not higher compared to the other 54 patients without ICDs. There was no correlation with the frontal lobe dysfunction and the electrode position in the subthalamus. Conclusion STN DBS improves baseline ICDs and results in the development of “transient” de novo ICDs in the short-term. In addition, there is a unique group of the patients who develop ICDs a long time after DBS.

Background Subthalamic deep brain stimulation (STN-DBS) is a promising intervention for primary dystonia; however, evidence regarding its efficacy is lacking. Thus, a long-term follow-up is indispensable. Objective This trial was designed to examine the efficacy and consistency of subthalamic deep brain stimulation in patients with primary dystonia over the long term. Method This was a retrospective study involving 14 patients with primary dystonia who underwent STN-DBS and consented to a follow-up of at least 10 years. The Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and 36-item Short-Form General Health Survey were employed, at five time points (pre-operation [baseline], 1 month post-operation, 1 year post-operation, 5 years post-operation, and last follow-up), to assess improvement of dystonic symptoms and changes in quality of life. Outcomes All patients gained extensive clinical benefits from STN-DBS therapy, without experiencing serious adverse effects. Improvements of 59.0% at 1 month, 85.0% at 1 year, and 90.8% at 5 years after the operation, and up to 91.4% at the last follow-up, were demonstrated by movement evaluation with the BFMDRS. All patients achieved a substantial improvement in quality of life. Conclusion Subthalamic deep brain stimulation is an effective and persisting alternative to pallidal deep brain stimulation, and importantly, it is very safe even with extremely long-term chronic stimulation.

Background Shorter pulse widths than conventional pulse width settings may lead to reduction of side effects and therefore be a valuable therapeutic option for deep brain stimulation (DBS) in patients with essential tremor (ET). Objective To compare the DBS effect of shorter pulse width at 40 μs (DBS-40 μs) to conventional pulse width at 60 μs (DBS-60 μs) on the therapeutic window in ET patients. Methods For this prospective, randomized, double-blind, crossover study 9 ET patients with chronic DBS of the ventral intermediate nucleus (VIM)/posterior subthalamic area (PSA) were recruited. Therapeutic window was calculated by determining efficacy and side effect thresholds for DBS-40 μs and DBS-60 μs. Tremor Rating Scales and Kinesia tremor analyses were used to compare clinical efficacy between the considered settings and deactivated DBS (DBS-OFF). Volume of neural activation (VNA) was calculated for both efficacy and side effect thresholds at each pulse width. Results DBS-40 μs showed a significantly larger therapeutic window than DBS-60 μs mainly due to higher side-effect thresholds. Both conditions significantly improved tremor compared to DBS-OFF, while efficacy was comparable between DBS-40 μs and DBS-60 μs. Moreover, VNA at efficacy threshold was smaller and less energy was required for tremor suppression with DBS-40 μs compared to DBS-60 μs. Conclusions VIM/PSA-DBS with short pulse width represents a promising programming option for DBS in ET as it reduces side effects while maintaining efficient tremor suppression. Furthermore, our data support the notion of pulse width dependent selective modulation of distinct fiber tracts leading to widening of the therapeutic window.

Objectives: The correct positioning of deep brain stimulation electrodes determines the success of surgery. In this study, we attempt to validate transcranial sonography (TCS) as a method for early postoperative confirmation of electrode location in the subthalamic nucleus (STN). Materials and Methods: Nineteen patients diagnosed with Parkinson's disease were enrolled in the study. Postoperative TCS was applied to measure the distance between the implanted electrodes and the third ventricle in the axial plane. Whether the electrodes were positioned within or outside the substantia nigra (SN) was evaluated through measurements in the coronal plane. The obtained metrics through TCS were compared with those from postoperative computed tomography (CT) and magnetic resonance imaging (MRI). Results: A statistically significant correlation between distances from electrode to third ventricle by TCS and CT/MRI (r = 0.75, p < 0.01) was observed. Distances from third ventricle to electrodes tips were different when sonographically they showed to be inside or outside the SN (p < 0.01). A cut-off value of 8.85mm in these distances was the most sensitive (100%) and specific (90.5%) to predict if electrodes were positioned inside the SN (CI 95% 0.81-10.30,p = 0.001). Conclusions: Transcranial sonography is a useful technique to reliably identify targeted positioning of deep brain stimulation electrodes in or out of the SN.

Objectives The aim of this study was to report on four patients with craniocervical dystonia (CCD) treated with deep brain stimulation (DBS). In addition, we investigated the treatment efficacy and surgical outcome predictors by the review and analysis of previously published studies. Methods Four patients with CCD underwent DBS of the globus pallidus internus (Gpi) or subthalamus nucleus (STN). PubMed and MEDLINE searches were performed to obtain detailed information on patients who underwent DBS for CCD. The primary efficacy endpoint was the change in the Burke–Fahn–Marsden Dystonia Rating Scale (movement and disability scores, BFMDRS-M/D) after surgery. Results Seventy-five patients were included in the pooled analysis, including 69 patients with Gpi-DBS and 6 patients with STN-DBS. The mean follow-up of time was 28.0 months after surgery. The mean BFMDRS-M score was 24.5 ± 11.2 preoperatively and 8.1 ± 5.7 postoperatively at the final follow-up evaluation, with a mean improvement of 66.9% (p < 0.001). The mean BFMDRS-D score was 8.1 ± 4.6 preoperatively and 3.6 ± 2.5 postoperatively, with a mean percentage improvement of 56.0% (p < 0.01). Positive correlations were found between each of the preoperative movement and disability scores and percentage of postoperative improvement (r = 0.247, p = 0.034; r = 0.331, p = 0.034, respectively). Conclusion GPi/STN-DBS is an effective treatment for patients with medically refractory CCD, including those with severe preoperative symptoms. The age at CCD onset and the disease duration do not predict improvement in movement scores.

Subthalamotomy allows a reduction of doses of l-DOPA in dyskinetic patients while its antiparkinsonian benefits are preserved. However, the mechanisms of the potentiation of this response to medication remain to be elucidated. Hence, dopamine D1 and D2 receptors as well as the dopamine transporter were investigated using receptor binding autoradiography. D1 and D2 receptors as well as preproenkephalin and preprodynorphin mRNA levels were measured by in situ hybridization. Four dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian monkeys that underwent unilateral subthalamotomy were compared to four controls, four saline-treated and four l-DOPA-treated MPTP monkeys. Dopamine, its metabolites and its transporter were extensively and similarly decreased in all parkinsonian monkeys. D1 receptor specific binding was decreased in the striatum of all MPTP monkeys. The l-DOPA-induced decrease in D1 receptor specific binding was reversed in the striatum ipsilateral to subthalamotomy. D1 receptor mRNA levels followed a similar pattern. D2 receptor specific binding and mRNA levels remained unchanged in all groups. Striatal preproenkephalin mRNA levels were overall increased in MPTP monkeys; the STN-lesioned parkinsonian group had significantly lower values than the saline-treated and l-DOPA-treated parkinsonian monkeys in the dorsolateral putamen. Striatal preprodynorphin mRNA levels remained unchanged in MPTP monkeys compared to controls whereas it increased in all monkeys treated with l-DOPA compared to controls; subthalamotomy induced a decrease in the dorsolateral putamen ipsilateral to surgery. The improved motor response to l-DOPA after subthalamotomy in the parkinsonian monkeys investigated may be associated with an increased synthesis and expression of D1 receptors ipsilateral to STN lesion of the direct pathway.

A common consequence of spinal cord injury (SCI) is the development of severe, debilitating neuropathic pain. The pain is spontaneous and persistent in the absence of an insult, but it can also present as hypersensitivity to painful stimuli (hyperalgesia) and hypersensitivity to normally innocuous stimuli (allodynia).12,13 Unfortunately, current treatments cannot produce complete relief of the pain and are not effective in all patients.2,14 One potential treatment, motor cortex stimulation (MCS), was serendipitously found to reduce neuropathic pain in patients.55,56 Since then, MCS has been proposed for the treatment of other chronic neuropathic pain conditions including SCI pain,48–51,58 and several noninvasive MCS protocols have been developed; these include transcranial magnetic stimulation and transcranial direct current stimulation.23,28 Some authors report that MCS results in pain relief in approximately 50% of the patients24; however, evidence from placebo-controlled trials to support these claims is lacking.10 Pain relief occurs progressively after the onset of MCS19 and persists after the stimulation has stopped. This poststimulation effect can last from minutes to days in some patients21,22 and suggests that MCS could potentially serve as a therapy for treatment-resistant neuropathic pain. However, the mechanisms by which MCS alleviates pain remain poorly understood. Recently, we described a novel system for the regulation of nociceptive processing in the thalamus, the incertothalamic system.31 In this system, the zona incerta (ZI; a GABAergic nucleus located in the diencephalon) inhibits the flow of nociceptive and somatosensory information in the posterior thalamus (Po),31,54 and this inhibition is regulated by the cholinergic system.32 In animals with SCI, we demonstrated that hypersensitivity is associated with an abnormally reduced inhibition from ZI.31 The reduced inhibition results in enhanced spontaneous and evoked activity in higher order thalamic nuclei (Po) and cortical structures involved in nociceptive processing.31,43,45 In the same animals, we found that MCS reverses spontaneous painlike behaviors and hypersensitivity without having an effect on motor performance.11,27 We also found that electrical stimulation of ZI mimics MCS effects and that reversible inactivation of ZI blocks antinociception produced by MCS, suggesting an integral role for the ZI in mediating MCS effects.27 Because the main input to ZI is from frontal cortical areas, and in particular the motor cortex (M1),33,34 and because ZI projects densely upon Po,3,53 we hypothesized that antinociceptive effects of MCS are due to the activation of the incertothalamic pathway.

Objective Mild traumatic brain injury due to contact sports may cause chronic behavioral, mood, and cognitive disturbances associated with pathological deposition of tau protein found at brain autopsy. To explore whether brain tau deposits can be detected in living retired players, we used positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP). Methods Five retired National Football League players (age range: 45 to 73 years) with histories of mood and cognitive symptoms received neuropsychiatric evaluations and FDDNP-PET. PET signals in subcortical (caudate, putamen, thalamus, subthalamus, midbrain, cerebellar white matter) and cortical (amygdala, frontal, parietal, posterior cingulate, medial and lateral temporal) regions were compared with those of five male controls of comparable age, education, and body mass index. Results FDDNP signals were higher in players compared with controls in all subcortical regions and the amygdala, areas that produce tau deposits following trauma. Conclusions The small sample size and lack of autopsy confirmation warrant larger, more definitive studies, but if future research confirms these initial findings, FDDNP-PET may offer a means for premorbid identification of neurodegeneration in contact-sports athletes.

Deep brain stimulation (DBS) is considered an established treatment for advanced Parkinson’s disease (PD). Nevertheless, some questions remain open. As different nuclei have been stimulated producing a wide number of effects on motor and non-motor symptoms, the first question relates to the issue of which target should be considered. Long-term and convincing data are available on the effects of subthalamus (STN), globus pallidus internus (GPi), and nucleus ventralis intermedius (Vim) of thalamus whereas less evidences have been collected on other deep brain targets, such as pedunculopontine nucleus, centromedian/parafascicular thalamic complex or zona incerta. A recent trial comparing STN and GPi DBS has not shown any substantial differences between both targets and the reasons for this are still unknown. Indeed most clinicians prefer the STN because of its better motor effect and the potential to reduce drug treatment as suggested by several smaller studies. On the other hand, preliminary data suggest a possibly better effect of GPi-stimulation on gait. Smaller studies also suggest advantages for dyskinetic and possibly older patients for the Gpi as a target. The next question is if earlier treatment may improve the course of PD. A small pilot study was positive and modeling of the effects of DBS earlier in the course of the disease supported such an approach but the pivotal study is still lacking.

Imaging studies of serotonin transporter binding or tryptophan retention in autistic patients suggest that the brain serotonin system is decreased. However, treatment with drugs which increase serotonin (5-HT) levels, specific serotonin reuptake inhibitors (SSRIs), commonly produce a worsening of the symptoms. In this study we examined 5-HT axons that were immunoreactive to a serotonin transporter (5-HTT) antibody in a number of postmortem brains from autistic patients and controls with no known diagnosis who ranged in age from 2 to 29 years. Fine, highly branched, and thick straight fibers were found in forebrain pathways (e.g. medial forebrain bundle, stria terminalis and ansa lenticularis). Many immunoreactive varicose fine fibers were seen in target areas (e.g. globus pallidus, amygdala and temporal cortex). Morphometric analysis of the stained axons at all ages studied indicated that the number of serotonin axons was increased in both pathways and terminal regions in cortex from autism donors. Our findings provide morphological evidence to warrant caution when using serotonin enhancing drugs (e.g. SSRIs and receptor agonist) to treat autistic children. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.

Purpose Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been the mainstream surgical procedure for advanced Parkinson’s disease (PD) during the last decade. Reports from a few individual centres have hinted that women who receive STN DBS are under-represented. We aimed to evaluate the gender distribution of patients with PD who had received STN DBS during the last ten years, and to discuss the findings in relation to studies on gender prevalence of PD. Methods A search of the PubMed database of clinical papers in English language related to STN DBS between 2000 and 2009 was conducted. Care was taken to minimize redundancies in reporting of published patients. The proportion of men and women were expressed in total and according to pre-defined geographic regions. Results One hundred and thirty five papers were eligible for review. The gender of the patients was specified in 119 papers on a total of 3880 patients, of which 63% were men. According to geographic origin of publications, the percentage of men with STN DBS was 68% in North America, 62% in Europe, 69% in Australia and 50% in Asia. Conclusions The proportion of male patients who undergo STN DBS seems to exceed the reported male/female ratio of patients with PD.

This study aimed at investigating the neuropsychological effect of DBS of the Subthalamic Nucleus in patients with advanced Parkinson's disease (PD).A standardized neuropsychological test battery, assessing reasoning, memory and executive functions, was administered to 27 PD patients who underwent DBS-STN (DBS group) and to a matched control group of 31 PD patients under optimal medical treatment (MED group). Patients were evaluated at baseline and at the end of 1 year.Change score analysis (T1 minus T0 scores) demonstrated a significant decline in phonemic verbal fluency in the DBS group compared with the MED group (p0.005), while there were no significant changes between the two groups for the other cognitive tests. Single cases analysis by means of multivariate normative comparisons revealed that 4 out of 27 DBS patients (15%) showed cognitive deterioration one year post surgery. These patients were significantly more compromised from a motor standpoint (UPDRS, section III) than the 23 DBS PD patients who had no cognitive decline post surgery.Results of this prospective controlled-study showed that phonemic verbal fluency declined one year after DBS-STN, while the other cognitive domains did not change significantly. Nevertheless, single case analysis highlighted the fact that a subgroup comprising 15% of DBS-STN patients (4/27) showed significant cognitive decline 1 year after surgery.

Galanin-like peptide (GALP) is located in the arcuate nucleus (Arc) of the hypothalamus and is known to regulate both food intake and sexual behaviors in adult male rats. We have previously demonstrated that ICV GALP administration elicits a significant fos response within the medial preoptic area (mPOA). GALP is known to stimulate both food intake and male-typical sex behavior, presumably by direct actions within the mPOA. Recent data from our and other labs have led us to suspect that GALP effects on sex behaviors are due to activation of incertohypothalamic dopaminergic neurons that terminate within the mPOA. To test the hypothesis that GALP activates mPOA dopaminergic systems, we utilized an immunolesion technique to eliminate dopaminergic fiber input to the mPOA via a dopamine transporter-specific toxin (DATSAP, n=8) and compared to control injections (SAP, n=8). All animals were sexually experienced adult male Long-Evans rats. DATSAP-treated male rats showed a significant (p0.001) reduction in male sexual behaviors compared to SAP controls. We found that elimination of dopaminergic fibers within the mPOA significantly (p0.001) eliminated all aspects of male sexual behavior under normal mating paradigms. Injections of GALP (5.0 nmol) significantly increased (p0.01) male sex behavior and food intake in SAP control male rats but GALP did not stimulate the expression of these behaviors in DATSAP-treated rats. The orexigenic and anorexigenic effects of GALP were significantly (p0.001) attenuated in DATSAP-treated male rats compared to SAP controls; however, ICV GALP was still able to significantly (p0.05) reduce 24h body weight in both DATSAP and SAP rats. ICV GALP significantly (p0.05) stimulated fos within the mPOA of SAP rats but not in DATSAP-treated male rats. These data suggest that GALP activates feeding and sexual behaviors in male rats by stimulating dopaminergic neurons that terminate within the mPOA.

The ventral part of the oral pontine reticular nucleus (vRPO) is a demonstrated site of brainstem REM-sleep generation and maintenance. The vRPO has reciprocal connections with structures that control other states of the sleep-wakefulness cycle, many situated in the basal forebrain and the diencephalon. Some of these connections utilize the inhibitory neurotransmitter GABA. The aim of the present work is to map the local origin of the basal forebrain and diencephalon projections to the vRPO whether GABAergic or non-GABAergic. A double-labelling technique combining vRPO injections of the neuronal tracer, cholera-toxin (CTB), with GAD-immunohistochemistry, was used for this purpose in adult cats. All of the numerous CTB-positive neurons in the reticular thalamic and dorsocaudal hypothalamic nuclei were double-labelled (CTB/GAD-positive) neurons. Approximately 15%, 14% and 16% of the CTB-positive neurons in the zona incerta and the dorsal and lateral hypothalamic areas are, respectively, CTB/GAD-positive neurons. However, only some double-labelled neurons were found in other hypothalamic nuclei with abundant CTB-positive neurons, such as the paraventricular nucleus, perifornical area and H1 Forel field. In addition, CTB-positive neurons were abundant in the central amygdaline nucleus, terminal stria bed nuclei, median preoptic nucleus, medial and lateral preoptic areas, dorsomedial and ventromedial hypothalamic nuclei, posterior hypothalamic area and periventricular thalamic nucleus. The GABAergic and non-GABAergic connections described here may be the morphological pillar through which these prosencephalic structures modulate, either by inhibiting or by exciting, the vRPO REM-sleep inducing neurons during the different sleep-wakefulness cycle states.

The early motor manifestations of Parkinson’s disease (PD) reflect degeneration of nigrostriatal dopamine neurons projecting to the caudal putamen. However, extrastriatal dopamine and other monoamine systems are also involved, particularly in later disease. We used 18F-dopa PET in a cross-sectional study to characterize extrastriatal monoamine neuronal dysfunction in PD. 16 Controls and 41 patients underwent investigation. We found that 18F-dopa uptake was decreased in cortical motor areas, particularly the motor cortex, even in early disease. Frontal association areas were also affected in later disease but limbic areas were spared except for hypothalamus. The substantia nigra, midbrain raphe and locus coeruleus showed normal or increased 18F-dopa uptake until PD was advanced, indicating compensatory responses in intact monoamine neuron perikarya. The red nucleus, subthalamus, ventral thalamus and pineal gland were also eventually involved. These findings provide a further basis for understanding the complex pathophysiology of PD in vivo and complement pathological studies.

To investigate the time span within which bradykinesia re-occurs, we registered movement parameters immediately after the termination of deep brain stimulation of the subthalamic nucleus (STN) in nine Parkinson patients with chronically implanted bilateral STN electrodes. Two repetitive movements were investigated: finger-tapping and forearm pronation-supination. When stimulation was switched off, the amplitude and velocity of the investigated movements significantly declined, but the frequency did not. The time course of this decline was modeled by an exponential function that yielded time constants between 15 and 30s. The effect of stimulation had completely disappeared within 1 min. These results suggest that it is necessary to wait at least for 1 min after the end of stimulation before performing further assessments.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective for the treatment of advanced Parkinson's disease. Most studies have evaluated the effectiveness of DBS of the STN using clinical motor scores or simple timed tests of motor function. There have been few studies that quantitatively assessed the outcome of STN DBS using multiple testing paradigms. In the current study, 11 patients who had bilateral STN DBS were quantitatively evaluated under four conditions using gait, postural control, and gait initiation. The four conditions included the medication on/stimulation on (M_on/S_on), medication on/stimulation off (M_on/S_off), medication off/stimulation on (M_off/S_on), and medication off/stimulation off (M_off/S_off) conditions. DBS of the STN significantly increased walking speed with and without levodopa, but had no influence on the cadence. The addition of levodopa had a minimal additional effect on walking speed. The effect of STN DBS on gait initiation approached the significant level. The mean values of lateral body sway during quiet standing increased moderately with medication and/or DBS, but the changes were not statistically significant. Future studies need to determine whether or not there is a potential negative effect of STN DBS on the postural control.

Recent studies show that the placebo component of a treatment can be investigated by administering therapies either overtly or covertly, without the administration of any placebo. Here, we analyze the effects of open (i.e., expected) versus hidden (i.e., unexpected) stimulations of the human subthalamic region on autonomic responses in Parkinson patients. To do this, we mapped the whole subthalamic region, from the dorsal to the ventral part, and recorded both heart rate and sympathetic responses by using spectral analysis of heart rate variability. We found that open stimulations were more effective than hidden ones only in the ventral subthalamic region, whereas no difference between the two conditions was found in the dorsal aspect. By analyzing the stimulus-response curves in the dorsal, middle, and ventral subthalamic regions, we found that the autonomic response threshold was higher in the hidden than open condition for both heart rate and sympathetic responses only in the ventral part. As this ventralmost portion of the subthalamic region is involved in associative-limbic functions, these data suggest that expectation enhances autonomic responses only if these are elicited in the limbic system. These results extend previous findings on the open-hidden paradigm in deep brain stimulation [Benedetti, F., Colloca, L., Lanotte, M., Bergamasco, B., Torre, E., Lopiano, L., 2004a. Autonomic and emotional responses to open and hidden stimulations of the human subthalamic region. Brain Res. Bull. 63, 203-211.], and indicate that expectation plays a major role in the therapeutic outcome. In light of the interactions between the sympathetic adrenergic system and the immune system, the open-hidden difference in autonomic responses might be relevant to the understanding of how expectations might affect the immune system.

Sleep deprivation increases sleep propensity in rats and mice as well as the production of several sleep-regulatory substances. Nuclear factor kappa B (NF-kappa B) is a transcription factor implicated in the activation of many of these sleep-promoting substances. A unique population of neurons immunoreactive for the p65 subunit of NF-kappa B was previously localized within the caudal dorsolateral hypothalamus of rats. Therefore, we evaluated the effect of sleep deprivation on NF-kappa Bp65-immunoreactivity (IR) in cells of this region in rats as well as its nuclear translocation in a kappa B-lacZ transgenic mouse line. In rats after 6 h of sleep deprivation beginning at light onset, the number of neurons with NF-kappa Bp65-IR increased significantly in the caudal lateral hypothalamus, specifically the magnocellular lateral hypothalamus adjacent to the subthalamus. Sleep deprivation also significantly increased the number of cells expressing NF-kappa B-dependent beta-galactosidase in the magnocellular lateral hypothalamus, zona incerta dorsal, as well as the adjacent subthalamus in the transgenic mice. These results suggest that NF-kappa B expressing cells within the lateral hypothalamus may be important in the maintenance of the sleep-wake cycle.

We performed a microstimulation study of the subthalamic region of Parkinsonian patients who underwent bilateral electrode implantation in the subthalamic nuclei and whose heart rate and heart rate variability were recorded. The stimulation of the dorsalmost region, which includes the zona incerta and the dorsal pole of the subthalamic nucleus, produced autonomic responses that were constant over time. In fact, hidden stimulations (the patient is not aware of being stimulated) and open stimulations (the patient is aware of being stimulated) always induced the same responses. By contrast, the stimulation of the ventralmost region, which includes the ventral pole of the subthalamic nucleus and the substantia nigra pars reticulata, produced autonomic and emotional responses that were inconstant over time and varied according to the condition. In fact, different responses were elicited with hidden and open stimulations. These data suggest that the dorsal subthalamic nucleus and/or the zona incerta are involved in autonomic control, whereas the ventral subthalamic nucleus and/or the substantia nigra reticulata are involved in associative/limbic-related autonomic activity. The difference between the open and hidden stimulations in the ventral subthalamic region can explain previous studies in which open and hidden stimulations produced different therapeutic outcomes.

Bilirubin toxicity remains a significant problem despite recent advances in the care of jaundiced (hyperbilirubinemic) neonates. A recent surge in reported cases of classical kernicterus, due in part to earlier hospital discharge and relaxation of treatment criteria for hyperbilirubinemia, and new reports of hyperbilirubinemia-induced auditory dysfunction using evoked potential based infant testing and hearing screening, underscore the need to better understand how hyperbilirubinemia causes brain damage in some infants, especially because the damage is preventable. Recent progress in understanding bilirubin binding and neurotoxicity resulting from unbound or "free" unconjugated bilirubin, how bilirubin affects the central nervous system in vivo and in vitro, and the use of new clinical tools in neonates, for example magnetic resonance imaging revealing bilateral lesions in globus pallidus and subthalamus, and abnormal brainstem auditory evoked potentials with normal inner ear function, may lead to improved detection and prevention of neurologic dysfunction and damage from bilirubin. Finally, the concern is raised that partial or isolated neurologic sequelae, for example auditory neuropathy and other central auditory processing disorders, may result from excessive amount and duration of exposure to free, unconjugated bilirubin at different stages of neurodevelopment.

Recent studies have provided many lines of evidence that specific homeodomain factors act to regulate differentiation into specific neuron types. However, these studies have mainly focused on the caudal CNS, while in the forebrain, the regulation of neuron specification remains relatively unknown. To investigate the genetic regulatory networks that control neuron differentiation in the forebrain, we have analyzed the expression patterns and functions of DLX homeodomain factors in the ventral thalamus of early mouse embryos. During initial neurogenesis (E9.5-E10.5), DLX(+) cells are the first progenitors to make terminal divisions and differentiate as neurons. We have defined a set of regulatory genes coexpressed with DLX, in both progenitors (PAX6 and MASH1) and in the differentiating neurons (PAX6, along with a combination of LIM-type homeodomain factors, including ISL1, Lhx1/Lim1, and Lhx5/Lim2). These initial neurons express tyrosine hydroxylase (TH), and become the PAX6-expressing A13 dopaminergic neurons of the zona incerta. To test for DLX function, the initial differentiation of the ventral thalamic neurons was examined in embryos mutant for Dlx1 and Dlx2. Dlx1/2 double homozygous mutants formed ventral thalamic neurons, but these neurons lacked PAX6, ISL1, and TH expression. These data suggest that DLX genes act as forebrain-specific factors linking general neuron-inducing signals to region-specific neuron differentiation programs.

The melanin-concentrating hormone and neuropeptide glutamic acid-isoleucine are expressed in neurons located mainly in the hypothalamus that project widely throughout the CNS. One of the melanin-concentrating hormone main targets is the medial mammillary nucleus, but the exact origin of these fibers is unknown. We observed melanin-concentrating hormone and neuropeptide glutamic acid-isoleucine immunoreactive fibers coursing throughout the mammillary complex, showing higher density in the pars lateralis of the medial mammillary nucleus, while the lateral mammillary nucleus showed sparse melanin-concentrating hormone innervation. The origins of these afferents were determined by using implant of the retrograde tracer True Blue in the medial mammillary nucleus. Double-labeled neurons were observed in the lateral hypothalamic area, rostromedial zona incerta and dorsal tuberomammillary nucleus. A considerable population of retrogradely labeled melanin-concentrating hormone perikaryal profiles was also immunoreactive to neuropeptide glutamic acid-isoleucine (74+/-15% to 85+/-15%). The afferents from the lateral hypothalamic area, rostromedial zona incerta and dorsal tuberomammillary nucleus to the medial mammillary nucleus were confirmed using implant of the anterograde tracer Phaseolus vulgaris leucoagglutinin. In addition, using double-labeled immunohistochemistry, we found no co-localization between neurons expressing melanin-concentrating hormone and adenosine deaminase (histaminergic marker) in the dorsal tuberomammillary nucleus. We hypothesize that these melanin-concentrating hormone projections participate in spatial memory process mediated by the medial mammillary nucleus. These pathways would enable the animal to look for food during the initial moments of appetite stimulation.

We have previously shown the involvement of the ventromedial nucleus of the hypothalamus (VMH) in inducing running behavior. Stimulation of kainate (KA)-type glutamate receptors in the unilateral VMH of the rat exclusively elicited stereotyped running behavior. However, the neural pathways or functional connections of the VMH neurons involved in the running activity are yet to be elucidated further. In this study we examined whether the subthalamic locomotor region (SLR) is involved in the expression of the running activity originating in the VMH. The multiunit activity (MUA) in the ipsilateral SLR was significantly increased by KA injection into the VMH of urethane-anesthetized animals. Concomitant injection of 6,7-dinitroquioxalline-2,3-dione (DNQX, a KA-type glutamate receptor antagonist) with KA blocked this change in the MUA. Unilateral pre-injection of either kynurenate (non-selective glutamate receptor antagonist), D-2-amino-5-phosphonovalerate (AP5, an NMDA-type glutamate receptor antagonist) or DNQX into the SLR blocked the expression of the running activity induced by KA injection into the ipsilateral VMH. Results from the present study suggest that communication between KA-sensitive efferents from the VMH to glutamatergic pathways acting via NMDA and non-NMDA receptors in the SLR may underlie expression of running behavior originating in the VMH.

Objectives : Recently, bursts of high-frequency (1000 Hz) median nerve somatosensory evoked potential (SEP) wavelets were recorded subcortically near and inside the thalamus from deep brain electrodes implanted for tremor therapy. This study aimed to clarify whether these subcortical SEP bursts reflect evoked axonal volleys running in the thalamocortical radiation or a locally restricted intrathalamic response. Methods : During deep brain electrode implantation, median nerve SEP were recorded in 7 patients sequentially along the subcortical stereotactic trajectory at sites +20 and +10 mm above the respective target nucleus (ventral intermediate thalamus or nucleus subthalamicus). Low- and high-frequency SEP components (corner frequency 430 Hz) were analyzed separately with respect to peak latency and amplitude as they changed along the recording trajectory. Results : Individual wavelets of the subcortical 1000 Hz SEP burst showed fixed peak latencies independent from the depth of the electrode penetration; they increased markedly in amplitude with decreasing distance to the thalamus. In contrast, the amplitude gradient between the two recording sites was shallower for the low-frequency SEP component, which peaked earlier at the lower recording site. Conclusions : Subcortically recorded 1000 Hz SEP wavelet bursts predominantly reflect locally restricted near-field activity, presumably generated in the somatosensory relay nucleus. In contrast, the variable peak latency of the subcortical low-frequency component could reflect postsynaptic potentials sequentially evoked during passage of the lemniscal afferences curving through the thalamus and contributions from the thalamocortical radiation.

Extracellular single-unit recordings were made from neurons in the lateral hypothalamus (LH) or zona incerta (ZI) of conscious sheep. A small population of neurons (12/83) were found which responded with increased firing rate when the animal looked at food but did not respond when the sheep looked at water. The effects of rapidly inducing intense thirst by the intracerebroventricular (i.c.v.) injection of hypertonic (0.85 M) saline or 200 ng of angiotensin II, or a mixture of the two dipsogenic stimuli, on the response of neurons initially responding only to the sight of food were investigated. Following i.c.v. injection of the dipsogenic stimuli the neurons began to respond strongly to the sight of water. The results demonstrated that changing the animal’s motivational state alters the response of some neurons in the LH and ZI and suggests that the neuronal response is influenced by the animal’s dominant need at the time of testing.

Stereotactic neurosurgery aims at placing therapeutic lesions or chronic stimulating electrodes at very precise locations within the brain. Microelectrode recording and macrostimulation are used in addition to anatomoradiological techniques to optimize targeting. Recently, the usefulness of electrophysiological procedures has been questioned. Based on more than 500 therapeutic stereotactic lesions in the last 10 years at the thalamic and subthalamic levels, we evaluate here retrospectively the utility of the two electrophysiological procedures. In two of the three stereotactic targets considered in this study, intraoperative electrophysiological confirmation is mandatory because of the target size with respect to interindividual anatomical variations and of the more or less close vicinity of eloquent structures.

The subthalamic nucleus (STN) is a key nucleus in the basal ganglia motor circuit that provides the major glutamatergic excitatory input to the basal ganglia output nuclei. The STN plays an important role in the normal motor function, as well as in pathological conditions such as Parkinson's disease. Development of a complete understanding of the role of the STN in motor control will require a detailed understanding of the mechanisms involved in the regulation of excitatory and inhibitory synaptic transmission in this nucleus. Here, we report that activation of groups I or III metabotropic glutamate (mGlu) receptors, but not group II, causes a depression of excitatory transmission in the STN. In contrast, mGlu receptor activation has no effect on the inhibitory transmission in this nucleus. Further characterization of the group I mGlu receptor-induced effect on EPSCs suggests that this response is mediated by mGlu1 and not mGlu5. Further, paired pulse studies suggest that both the mGlu1 receptor and the group III mGlu receptor-mediated effects are due to a presynaptic mechanism. If these receptors are involved in endogenous synaptic transmission in the STN, these results raise the exciting possibility that selective agents targeting mGlu receptors may provide a novel approach for the treatment of motor disorders involving the STN.

This study provides an analysis of the chemoarchitecture of the posterior hypothalamic area (PHA) and a retrograde transport analysis of inputs to the PHA in the rat. The chemoarchitectural analysis reveals that the majority of PHA neurons contain glutamate. Hypocretin, melanin concentrating hormone, tyrosine hydroxylase, neuropeptide Y and gamma-aminobutyric acid are also found in subsets of PHA neurons, and fibers immunoreactive for these substances as well as for serotonin, dopamine-beta-hydroxylase and met-enkephalin are observed in the area and aid in the delineation of its borders. The retrograde tracing study demonstrates that the PHA receives input from multiple, diverse neuron populations. Descending projections to the PHA arise from the limbic forebrain (cingulate cortex and lateral septum) and both the medial and lateral hypothalamus. Subcortical visual nuclei, including the ventral lateral geniculate nucleus and intergeniculate leaflet, pretectal area, and superior colliculus, and the subthalamus (zona incerta, fields of Forel) also project to the PHA. Ascending projections to the PHA arise from brainstem cholinergic nuclei, the reticular formation, midbrain raphe nuclei, periaqueductal gray and parabrachial nucleus. Retrograde transport studies using the psuedorabies virus (PRV) demonstrate that the PHA receives input indirectly from the hippocampus, amygdala and suprachiasmatic nucleus through circuits including nuclei in the limbic forebrain and hypothalamus. These data suggest that the PHA is important in the neural control of behavioral state, modulating aspects of hippocampal, autonomic and cortical function as they relate to the elaboration of adaptive behavior.

Chorea that occurs as a result of a stroke is rare. We report a patient who developed hemiplegia following an acute hemorrhagic stroke in the left cerebral peduncle and subthalamus; although he had recovered gradually from the severe limb weakness, monochorea occurred 6 months later. Pallidotomy eliminated this symptom and we found it is a safe treatment for medically intractable post-stroke chorea after hemiplegia has resolved.

Introduction: Subthalamic nucleus deep brain stimulation has become a useful tool in effectively treating severe Parkinson's disease. Method: While most reports in literature describe the immediate and short-term post-operative brain lead implant-related adverse events, we present the case of a 65-year-old man who developed herpes zoster (HZ) upon the subcutaneous placement of the pulse generator two years after the procedure. Conclusion: He had excellent recovery of HZ lesions and related pain after specific antiviral therapy. The importance of a correct diagnosis of this unusual complication is outlined in order to minimize the risk of debilitating chronic HZ-associated pain.

Previous reports have provided evidence of a reticulo-thalamic system, extending from the mesencephalic reticular formation (MRF) to the ventrolateral thalamus (VL), involved in the production of tremor. In humans, a funnel of fibers in the posterior subthalamus named the prelemniscal radiations (Raprl) has been described as an exquisite target to treat tremor in cases of Parkinson's disease. In the present study, a group of 14 patients suffering from Parkinson's disease, with prominent unilateral tremor and rigidity, were implanted with tetrapolar depth brain stimulation (DBS) electrodes in Raprl to perform chronic electrical stimulation (ES) for the treatment of patient symptoms. Electrodes were left externalized to corroborate their placement throughout MRI studies and also to perform the following electrophysiological battery: (a) recording of somatosensory-evoked responses (SEP) through different electrode contacts and scalp by means of a paradigm to study the attention process; (b) evoking scalp EEG responses by stimulation with low (3 cps, 6 cps) and high (60-120 cps) frequencies with stimuli delivered through different electrode contacts, and (c) studying recovery cycle (RC) potentials in the Raprl while the upper MRF was being stimulated and, conversely, the RC in MRF while Raprl was being stimulated, before and after subacute Raprl stimulation. Thereafter, the electrodes were internalized and connected to a pulse generator (IPG) to carry on chronic ES, while the effects of stimulation were determined through a quantitative evaluation that measured phasic and tonic muscular activity with EMG recordings during different motor tasks. Results indicate the following: (a) that late, but not early, SEP components were recorded in Raprl and modulated in different attentive conditions; (b) that bilateral recruiting responses and spike and wave complexes were elicited by Raprl through low-frequency stimulation, while bilateral positive DC shifts induced by high-frequency stimulation were recorded, similar to those obtained in animals from MRF, and (c) that Raprl-ES induced RC inhibition at Raprl, but Raprl ES did not change MRF-RC. Long-term Raprl-ES induced a significant decrease in tremor and rigidity. It was concluded that Raprl represents a subthalamic circuit electrophysiologically related to MRF in the genesis of tremor and rigidity and in the process of selective attention. Raprl-ES induced a significant improvement in tremor and rigidity by causing inhibition of the stimulated area.

Motor parkinsonism is characterised by bradykinesia, muscle rigidity, postural instability and resting tremor that occur most often in Parkinson's disease, multiple system atrophy and progressive supranuclear palsy. In all three disorders the main regulators of the caudate nucleus and putamen (dopaminergic substantia nigra and glutaminergic caudal intralaminar nuclei), as well as the cortical projection from the presupplementary motor area, degenerate. Degeneration of the major basal ganglia circuit neurons also occurs in multiple system atrophy, while degeneration of the subthalamus and a widespread loss of inhibitory interneurons within the extrapyramidal system occurs in progressive supranuclear palsy.

Surgical treatment of Parkinson's disease has become an important mode of therapy for advanced disease. Both ablative lesions and, more recently, deep brain stimulation have been employed. Various brain areas, including the thalamus, globus pallidus, and subthalamus, have been target sites.

Objective The subthalamic nucleus (STN) is an important motor and non-motor hub. Animal studies suggest that the STN is also involved in perception, however evidence in humans is missing. We analyzed the visuo-attentional activity of STN neurons in Parkinson‘s disease (PD) patients. Methods Extracellular neuronal activity and electrooculography was recorded during deep brain stimulation surgery from 12 awake PD patients (mean age 54.4 (SD 8.1) years) during presentation of 24 photographs, each shown for 2 s and preceded by a black screen. The action potentials elicited by watching photographs vs. black screen were compared using bootstrap. Results Of the 122 neurons detected, 34 were eye movement-related and excluded. The activity of 45 (51%) of the remaining 88 neurons was stimulus-specific ( P Conclusions The STN contains a surprisingly high ratio of neurons possibly involved in visuo-attentional processes. Key message Neurons of the STN are involved in visual perception and processing.

Summary In other experimental models, somatostatin (SRIF) helps coordinate central nervous system (CNS) activity associated with the response to stress. It also plays an important role in the effects of exercise, stress and bacterial infections on growth hormone (GH) release and it may interact with specific SRIF receptors found on lymphocytes. Pituitary GH is a potent immunomodulatory hor- mone which is important to normal function of the thymus and a wide range of immune defense mechanisms. This experiment mapped the distribution of immunoreactive (ir) SRIF in the basal forebrain of horses and ponies. Results are compared to those for other species in order to determine if the anatomical substrate for stress-dependant SRIF effects may be similar to that described for other animal models. Immersion fixed brain tissues were obtained from animals submitted for euthanasia and/or necropsy. Alternate sections were stained for ir-SRIF using characterized polyclonal SRIF antibody and the peroxidase-anti-peroxidase technique, as previously described. Distribution of SRIF cells and fibers was mapped on projection drawings following light microscopic examination. Tissues in this analysis included cell groups at the border between the telencephalon and the rostral diencephalon, the hypothalamus, caudate nucleus (n) subthalamus and thalamus. At rostral levels, ir-SRIF was widely dispersed throughout medial tissues. Caudally, pronounced immunoreactivity was found in ventromedial tissues. Reactive perikarya were localized in the caudate n, olfactory tuberculum, n of the lamina terminalis, rostral preoptic n, suprachiasmatic n, periventricular n, supraoptic n, paraventricular n, arcuate n and ventromedial n. Numerous SRIF fibers extended into the lateral septum, all preoptic n, paraventricular n, rostral hypothalamic n, dorsomedial n, ventromedial n and mammillary n. Reactive fibers were also found in midline thalamic n, perifomical areas, the zona incerta and the habenular n. This distribution is similar to that described in most vertebrates. It reflects the role of SRIF in multiple neurocrine interactions as well as its neuroendocrine activity. Results from this experiment suggest that equine SRIF is likely to participate in neural and endocrine pathways similar to that for other mammalian species. Similar localization patterns also suggest that the coordination of SRIF cell functions within the equine CNS may be comparable to that in other species. This suggests that studies in other species are likely to facilitate the characterization of control mechanisms for SRIF secretion in the equine species.

One commonly accepted idea is that affective aspects of pain sensation are derived from a flow of information from the spinal cord through the reticular formation to the intralaminar thalamus and subthalamus. Little is known, however, about the extent to which spinoreticular terminations and reticulodiencephalic neuronal cell bodies overlap. This study used a combination of anterograde and retrograde tracing techniques to compare these distributions in the cat. Whereas spinoreticular terminations were concentrated caudally and laterally, neurons projecting to intralaminar thalamus and subthalamus were concentrated rostrally and medially. Thus, information conveyed from the spinal cord to the reticular formation appears to have direct access to intralaminar thalamus and subthalamus only by way of a few widely scattered neurons. When considered with the results of others, these results encourage less emphasis on a putative spino-reticulo-diencephalic pathway for pain. Rather, the reticular formation's role in pain is more likely to involve its full complement of interconnected descending and ascending connections.

In male rats, ibotenic acid and N-methyl-D-aspartic acid were used to destroy neuronal perikarya intrinsic to an anterior-posterior continuum including the caudal zona incerta and lateral tegmentum. Some lesions virtually eliminated male sexual behavior - an effect most closely associated with damage to the lateral hypothalamus and zona incerta. Many lesioned males who copulated to ejaculation with normally active females showed little or no mating with receptive, but relatively inactive, females. Although it is possible to identify a critical region within the subthalamus whose destruction eliminates male sexual behaviour, sexually-relevant neuronal cell bodies appear to be distributed throughout the lateral hypothalamic/incertal/tegmental continuum.

A healthy, 66-year-old, right-handed man was admitted to our university hospital and diagnosed with herpes zoster ophthalmicus (HZO). After 4 weeks, he complained of hemichorea on his left side. Brain MRI showed a focal hemorrhage in the right subthalamic area. No evidence of aneurysmal lesion or cerebral angiitis was observed on cerebral angiography.

Introduction In parkinsonian 6-hydroxydopamine (6-OHDA)-lesioned animals the firing discharge of the globus pallidus (GP) and the substantia nigra reticulata (SNr) are in phase with urethane-induced slow wave cortex activity (SWA). The origin of this pathological synergy, hallmark of dopamine (DA) deficiency, is debated. In order to understand the role of SN pars compacta (SNc) signaling, we performed the electrocorticogram (ECoG) and single unit recordings from GP, SNr and subthalamus (STN), before and after the injection of tetrodotoxin (TTX) into the medial forebrain bundle (MFB). Results This procedure led to a dramatic reduction of the DA content in the striatum and promoted reversible contra-lateral akinesia. The TTX-mediated inactivation of MFB induced a fast developing coherence between cortex/GP and cortex/SNr and a significant increase of the cortex/STN synchronization. Interestingly, the long term ECoG/GP synchronization detectable in the 6-OHDA lesioned animals did not differ from the short term one induced controlaterally by the TTX block of MFB in the normal hemisphere. Intra-GP iontophoretic delivery of the D2 receptor antagonist haloperidol or the GABA A receptor antagonist bicuculline caused a short term induction of cortex/GP synchronization. Strikingly, STN inactivation by local muscimol reversed the TTX-mediated coherence between cortex and GP. Discussion Our data show that an abnormal and diffuse cortical/basal ganglia (BG) synchronization can be reproduced in absence of SNc neuronal loss and cytoarchitectonic alteration of the striatum. In addition, our results, difficult to reconcile with ex abrupto alterations of intra-striatal plasticity, seem compatible with acute changes of the functional interplay between cortex and the STN-GP pathway.

Comparisons of the descending pathways of the motor, visual and limbic cortex in the cat revealed a number of structures in di- and mesencephalon that receive projections from all these fields. They are centrolateral (CL), paracentral (Pc), central medial (CeM) and centre median (CM), nuclei of the thalamus, zona incerta (ZI) and Forel's field H1 of the subthalamus, nucleus of the posterior commissure and anterior and posterior nuclei of the pretectum (Prt), stratum griseum intermedial and profundum of superior colliculus (CS), periaqueductal gray matter (GC) and pontine nuclei (NP). The projections from the striate field of the visual cortex to ventrobasal complex of the thalamus (VB) are shown. The results are discussed with recent data on the anatomy and physiology. A possible role of corticocortical and corticofugal fiber connections is dealt with.

The [ 14 C]2-deoxy- d -glucose technique 33 was used to test the effects of central muscarinic stimulation on local cerebral glucose utilization (LCGU) in rats. Systemic administration of the muscarinic agonist oxotremorine (OXO, 0.7 mg/kg, ip) increased LCGU in brain regions involved in motor function: the sensorimotor cortex; the extrapyramidal motor system, including the striatum, globus pallidus, red nucleus, substantia nigra, subthalamus and ventral nucleus of the thalamus; the cerebellar vermis, fastigial nucleus and nucleus interpositus; and the vestibular nucleus. No effects were observed in the fibers of the pyramidal tract, internal capsule, cerebellar white matter and the dentate nucleus. Increases were not affected by the methylatropine (1 mg/kg sc), but were completely antagonized by scopolamine (2.5 mg/kg, ip). The anatomic distribution and magnitude of the LCGU response to OXO were not simply correlated with the reported densities of muscarinic receptors.

The sources and distribution of subcortical afferents to the anterior neocortex were investigated in the rat using the horseradish peroxidase technique. Injections into the prefrontal cortex labelled, in addition to the mediodorsal thalamic nucleus, neurons in a total of fifteen subcortical nuclei, distributed in the basal telencephalon, claustrum, amygdala, thalamus, subthalamus, hypothalamus, mesencephalon and pons. Of these, the projections from the zona incerta, the lateroposterior thalamic nucleus, and the parabrachial region of the caudal mesencephalon to the prefrontal cortex have not previously been described. Different parts of the mediodorsal thalamic nucleus project to different areas of the frontal cortex. Thus, horseradish peroxidase injections in the most ventral pregenual part of the medial cortex labelled predominantly neurons in the medial anterior and dorsomedial posterior parts of the mediodorsal nucleus; injections into the more dorsal pregenual area labelled only neurons in the lateral and ventral parts of the nucleus; injections placed supragenually labelled neurons in the dorsolateral posterior part of the nucleus; and injections into the dorsal bank of the anterior rhinal sulcus labelled neurons in the centromedial part of the nucleus. Several other subcortical nuclei had projections overlapping with that of the mediodorsal thalamic nucleus. Five different types of such overlap were distinguished: (1) cell groups labelled after horseradish peroxidase injections into one of the subfields of the projection area of the mediodorsal nucleus (defined as the prefrontal cortex), but not outside this area (parataenial nucleus of the thalamus); (2) cell groups labelled both after injection into a subfield of the projection area of the mediodorsal nucleus and after injections in a restricted area outside this area (anteromedial, ventral and laterposterior thalamic nuclei); (3) cell groups labelled after injections into all subfields of the mediodorsal nucleus projection area, but not outside this area (ventral tegmental area, basolateral nucleus of amygdala); (4) cell groups labelled after injections into any area of the anterior neocortex, including the mediodorsal nucleus projection area (parabrachial neurons of the posterior mesencephalon); (5) cell groups labelled after all neocortical injections investigated (claustrum, magnocellular nuclei of the basal forebrain, lateral hypothalamus, zona incerta, intralaminar thalamic nuclei, nuclei raphe dorsalis and centralis superior, and locus coeruleus). We can draw the following conclusions from these and related findings. First, because of the apparent overlap of projections of the mediodorsal, the anteromedial and ventral thalamic nuclei in the rat, parts of the prefrontal cortex can also be called ‘cingulate’ and ‘premotor’. Second, on the basis of projections from parts of the mediodorsal nucleus, the prefrontal cortex of the rat can be subdivided into areas corresponding to those in other species. Third, the neocortex receives afferents from a large number of subcortical cell groups outside the thalamus, distributed from the telencephalon to the pons; however, the prefrontal cortex seems to be the only neocortical area innervated by the ventral tegmental area and amygdala. Finally, neither the prefrontal cortex nor the mediodorsal thalamic nucleus receives afferents from regions directly involved in sensory and motor functions.

Horseradish peroxidase gel implants into either the nucleus raphe magnus (NRM) or inferior olive (IO) led to large numbers of retrogradely labeled cells in the prerubral subthalamic region in a cell group that surrounds the fasciculus retroflexus, which we suggest should be referred to as the nucleus parafascicularis prerubralis (nPfPr) to avoid the confusion of previous terminology. Autoradiographic studies, following injections of tritiated leucine into the nPfPr, confirmed projections to both medullary raphe nuclei (MRN) and IO. This common prerubral projection to IO, a well-established precerebellar nucleus, and MRN, again raises the question of whether the latter are involved in brainstem-mediated reflexes in addition to their well documented role in analgesic mechanisms.

Iontophoretic administration of PHA-L into the globus pallidus of rats resulted in the labeling of neuronal perikarya in the striatum as well as axons and terminals in the striatum, entopeduncular nucleus, subthalamus and substantia nigra. The labeled striatal perikarya were densely stained in Golgi fashion with virtually complete filling of the dendrites and spines. It is concluded that the striatal cells were filled by the retrograde transport of PHA-L and represent either striatopallidal cells, or striatonigral cells whose axons were interrupted as they passed through the injection site. The anterogradely labeled axon terminals in the striatum were observed in close apposition to the dendrites of the retrogradely labeled neurons suggesting the existence of synaptic contacts between the two groups of cells. This study demonstrates that PHA-L can be transported retrogradely as well as anterogradely following iontophoretic injections.