Deep brain stimulation and cognition: Translational aspects.

Many neurological patients suffer from memory loss. To date, pharmacological treatments for memory disorders have limited and short-lasting effects. Therefore, researchers are investigating novel therapies such as deep brain stimulation (DBS) to alleviate memory impairments. Up to now stimulation of the fornix, nucleus basalis of Meynert and entorhinal cortex have been found to enhance memory performance. Here, we provide an overview of the different DBS targets and mechanisms within the memory circuit, which could be relevant for enhancing memory in patients. Future studies are warranted, accelerating the efforts to further unravel mechanisms of action of DBS in memory-related disorders and develop stimulation protocols based on these mechanisms.

Amygdala stimulation ameliorates memory impairments and promotes c-Fos activity in fimbria-fornix-lesioned rats.

Recently we provided data showing that amygdala stimulation can ameliorate spatial memory impairments in rats with lesion in the fimbria-fornix (FF). The mechanisms for this improvement involve early gene expression and synthesis of BDNF, MAP-2, and GAP43 in the hippocampus and prefrontal cortex. Now we have studied which brain structures are activated by the amygdala using c-Fos as a marker of neural activation. First, we studied neuronal activation after tetanic stimulation to the amygdala in intact rats. We then carried out a second study in FF-lesioned rats in which the amygdala was stimulated 15 min after daily spatial memory training in the water maze. Our results showed that amygdala stimulation produces widespread brain activation, that includes cortical, thalamic, and brain stem structures. Activation was particularly intense in the dentate gyrus and the prefrontal cortex. Training in the water maze increased c-Fos positive nuclei in the dentate gyrus of the hippocampus and in medial prefrontal cortex. Amygdala stimulation to trained FF-lesioned rats induced an increase of neural activity in the dentate gyrus and medial prefrontal cortex relative to the FF-lesioned, but not stimulated group, like the c-Fos activity seen in trained control rats. Based on these and previous results we explain the mechanisms of amygdala reinforcement of neural plasticity and the partial recovery of spatial memory deficits.

Dissecting the Fornix in Basic Memory Processes and Neuropsychiatric Disease: A Review.

Background: The fornix is the primary axonal tract of the hippocampus, connecting it to modulatory subcortical structures. This review reveals that fornix damage causes cognitive deficits that closely mirror those resulting from hippocampal lesions. Methods: We reviewed the literature on the fornix, spanning non-human animal lesion research, clinical case studies of human patients with fornix damage, as well as diffusion-weighted imaging (DWI) work that evaluates fornix microstructure in vivo. Results: The fornix is essential for memory formation because it serves as the conduit for theta rhythms and acetylcholine, as well as providing mnemonic representations to deep brain structures that guide motivated behavior, such as when and where to eat. In rodents and non-human primates, fornix lesions lead to deficits in conditioning, reversal learning, and navigation. In humans, damage to the fornix manifests as anterograde amnesia. DWI research reveals that the fornix plays a key role in mild cognitive impairment and Alzheimer's Disease, and can potentially predict conversion from the former to the latter. Emerging DWI findings link perturbations in this structure to schizophrenia, mood disorders, and eating disorders. Cutting-edge research has investigated how deep brain stimulation of the fornix can potentially attenuate memory loss, control epileptic seizures, and even improve mood. Conclusions: The fornix is essential to a fully functioning memory system and is implicated in nearly all neurological functions that rely on the hippocampus. Future research needs to use optimized DWI methods to study the fornix in vivo, which we discuss, given the difficult nature of fornix reconstruction. Impact Statement The fornix is a white matter tract that connects the hippocampus to several subcortical brain regions and is pivotal for episodic memory functioning. Functionally, the fornix transmits essential neurotransmitters, as well as theta rhythms, to the hippocampus. In addition, it is the conduit by which memories guide decisions. The fornix is biomedically important because lesions to this tract result in irreversible anterograde amnesia. Research using in vivo imaging methods has linked fornix pathology to cognitive aging, mild cognitive impairment, psychosis, epilepsy, and, importantly, Alzheimer's Disease.

Topography of Cholinergic Changes in Dementia With Lewy Bodies and Key Neural Network Hubs.

OBJECTIVES: The authors investigated the topography of cholinergic vulnerability in patients with dementia with Lewy bodies (DLB) using positron emission tomography (PET) imaging with the vesicular acetylcholine transporter (VAChT) [18F]-fluoroethoxybenzovesamicol ([18F]-FEOBV) radioligand. METHODS: Five elderly participants with DLB (mean age, 77.8 years [SD=4.2]) and 21 elderly healthy control subjects (mean age, 73.62 years [SD=8.37]) underwent clinical assessment and [18F]-FEOBV PET. RESULTS: Compared with the healthy control group, reduced VAChT binding in patients with DLB demonstrated nondiffuse regionally distinct and prominent reductions in bilateral opercula and anterior cingulate to mid-cingulate cortices, bilateral insula, right (more than left) lateral geniculate nuclei, pulvinar, right proximal optic radiation, bilateral anterior and superior thalami, and posterior hippocampal fimbria and fornices. CONCLUSIONS: The topography of cholinergic vulnerability in DLB comprises key neural hubs involved in tonic alertness (cingulo-opercular), saliency (insula), visual attention (visual thalamus), and spatial navigation (fimbria/fornix) networks. The distinct denervation pattern suggests an important cholinergic role in specific clinical disease-defining features, such as cognitive fluctuations, visuoperceptual abnormalities causing visual hallucinations, visuospatial changes, and loss of balance caused by DLB.

Anatomy and function of the fornix in the context of its potential as a therapeutic target.

The fornix is a white matter bundle located in the mesial aspect of the cerebral hemispheres, which connects various nodes of a limbic circuitry and is believed to play a key role in cognition and episodic memory recall. As the most prevalent cause of dementia, Alzheimer's disease (AD) dramatically impairs the quality of life of patients and imposes a significant societal burden on the healthcare system. As an established treatment for movement disorders, deep brain stimulation (DBS) is currently being investigated in preclinical and clinical studies for treatment of memory impairment in AD by modulating fornix activity. Optimal target and stimulation parameters to potentially rescue memory deficits have yet to be determined. The aim of this review is to consolidate the structural and functional aspects of the fornix in the context of neuromodulation for memory deficits. We first present an anatomical and functional overview of the fibres and structures interconnected by the fornix. Recent evidence from preclinical models suggests that the fornix is subdivided into two distinct functional axes: a septohippocampal pathway and a subiculothalamic pathway. Each pathway's target and origin structures are presented, followed by a discussion of their oscillatory dynamics and functional connectivity. Overall, neuromodulation of each pathway of the fornix is discussed in the context of evidence-based forniceal DBS strategies. It is not yet known whether driving fornix activity can enhance cognition-optimal target and stimulation parameters to rescue memory deficits have yet to be determined.

Neurodevelopmental wiring deficits in the Ts65Dn mouse model of Down syndrome.

Down syndrome is the most common genetic cause of intellectual disability and occurs due to the trisomy of human chromosome 21. Adolescent and adult brains from humans with Down syndrome exhibit various neurological phenotypes including a reduction in the size of the corpus callosum, hippocampal commissure and anterior commissure. However, it is unclear when and how these interhemispheric connectivity defects arise. Using the Ts65Dn mouse model of Down syndrome, we examined interhemispheric connectivity in postnatal day 0 (P0) Ts65Dn mouse brains. We find that there is no change in the volume of the corpus callosum or anterior commissure in P0 Ts65Dn mice. However, the volume of the hippocampal commissure is significantly reduced in P0 Ts65Dn mice, and this may contribute to the impaired learning and memory phenotype of this disorder. Interhemispheric connectivity defects that arise during development may be due to disrupted axon growth. In line with this, we find that developing hippocampal neurons display reduced axon length in vitro, as compared to neurons from their euploid littermates. This study is the first to report the presence of defective interhemispheric connectivity at the time of birth in Ts65Dn mice, providing evidence that early therapeutic intervention may be an effective time window for the treatment of Down syndrome.

No relationship between fornix and cingulum degradation and within-network decreases in functional connectivity in prodromal Alzheimer's disease.

INTRODUCTION: The earliest changes in the brain due to Alzheimer's disease are associated with the neural networks related to memory function. We investigated changes in functional and structural connectivity among regions that support memory function in prodromal Alzheimer's disease, i.e., during the mild cognitive impairment (MCI) stage. METHODS: Twenty-three older healthy controls and 25 adults with MCI underwent multimodal MRI scanning. Limbic white matter tracts-the fornix, parahippocampal cingulum, retrosplenial cingulum, subgenual cingulum and uncinate fasciculus-were reconstructed in ExploreDTI using constrained spherical deconvolution-based tractography. Using a network-of-interest approach, resting-state functional connectivity time-series correlations among sub-parcellations of the default mode and limbic networks, the hippocampus and the thalamus were calculated in Conn. ANALYSIS: Controlling for age, education, and gender between group linear regressions of five diffusion-weighted measures and of resting state connectivity measures were performed per hemisphere. FDR-corrections were performed within each class of measures. Correlations of within-network Fisher Z-transformed correlation coefficients and the mean diffusivity per tract were performed. Whole-brain graph theory measures of cluster coefficient and average path length were inspecting using the resting state data. RESULTS & CONCLUSION: MCI-related changes in white matter structure were found in the fornix, left parahippocampal cingulum, left retrosplenial cingulum and left subgenual cingulum. Functional connectivity decreases were observed in the MCI group within the DMN-a sub-network, between the hippocampus and sub-areas -a and -c of the DMN, between DMN-c and DMN-a, and, in the right hemisphere only between DMN-c and both the thalamus and limbic-a. No relationships between white matter tract 'integrity' (mean diffusivity) and within sub-network functional connectivity were found. Graph theory revealed that changes in the MCI group was mostly restricted to diminished between-neighbour connections of the hippocampi and of nodes within DMN-a and DMN-b.

Diffusion weighted imaging evidence of extra-callosal pathways for interhemispheric communication after complete commissurotomy.

The integrity of white matter architecture in the human brain is related to cognitive processing abilities. The corpus callosum is the largest white matter bundle interconnecting the two cerebral hemispheres. "Split-brain" patients in whom all cortical commissures have been severed to alleviate intractable epilepsy demonstrate remarkably intact cognitive abilities despite the lack of this important interhemispheric pathway. While it has often been speculated that there are compensatory alterations in the remaining interhemispheric fibers in split-brain patients several years post-commissurotomy, this has never been directly shown. Here we examined extra-callosal pathways for interhemispheric communication in the brain of a patient who underwent complete cerebral commissurotomy using diffusion weighted imaging tractography. We found that compared with a healthy age-matched comparison group, the split-brain patient exhibited increased fractional anisotropy (FA) of the dorsal and ventral pontine decussations of the cortico-cerebellar interhemispheric pathways. Few differences were observed between the patient and the comparison group with respect to FA of other long-range intrahemispheric fibers. These results point to specific cerebellar anatomical substrates that may account for the spared interhemispheric coordination and intact cognitive abilities that have been extensively documented in this unique patient.

Fornical Closed-Loop Stimulation for Alzheimer's Disease.

Pharmacological neuromodulation strategies have shown limited efficacy in treating memory deficits related to Alzheimer's disease (AD). Despite encouraging results from a few preclinical studies, clinical trials investigating open-loop deep brain stimulation (DBS) for AD have not been successful. Recent refinements in understanding the various phases of memory processes, animal studies investigating phase-specific modulation of hippocampal activity during memorization, and clinical studies using closed-loop DBS strategies to treat patients with movement disorders, all point to the need to investigate closed-loop fornical DBS strategies to better understand memory dynamics and potentially treat memory deficits in AD preclinical models.

Delayed degeneration of the left fornical crus with verbal memory impairment in a patient with mild traumatic brain injury: A case report.

RATIONALE: We report on a patient who showed delayed degeneration of the left fornical crus with verbal memory impairment following mild traumatic brain injury (TBI), which was demonstrated by diffusion tensor tractography (DTT). PATIENT CONCERNS:: fter flexion and hyperextension of her head to the opposite side, the patient experienced a dazed feeling for a while at the time of head trauma. The patient's Glasgow Coma Scale score was 15, and mini-mental state examination score was 30. DIAGNOSES: A 50-year-old right-handed female with 12 years of education suffered from head trauma resulting from a car accident. INTERVENTIONS: A The patient showed normal memory function at one year after onset: the Memory Assessment Scale (global memory: 124 (95 percentile (%ile)), verbal memory: 111 (77%ile), and visual memory: 132 (98%ile) (A percentile is a measure used in statistics indicating the value below which a given percentage of observations in a group of observations fall). However, the patient began to experience decline of memory function such as forgetfulness at approximately 1.5 years after onset. On the 2-year evaluation, she showed decrement of memory function (global memory: 108 (70%ile), verbal memory: 86 (18%ile), and visual memory: 129 (97%ile). OUTCOMES: On 1-year DTT, the integrity of the fornix was well preserved between the fornical column and fornical crus. However, on 2-year DTT, a discontinuation was observed in the left fornical crus. LESSONS: Delayed degeneration of the left fornical crus was demonstrated in a patient who showed delayed onset of verbal memory impairment following mild TBI.

White matter abnormalities in the fornix are linked to cognitive performance in SZ but not in BD disorder: An exploratory analysis with DTI deterministic tractography.

BACKGROUND: In psychosis, white matter (WM) microstructural changes have been detected previously; however, direct comparisons of findings between bipolar (BD) and schizophrenia (SZ) patients are scarce. In this study, we employed deterministic tractography to reconstruct WM tracts in BD and SZ patients. METHODS: Diffusion tensor imaging (DTI) data was carried out with n=32 euthymic BD type I patients, n=26 SZ patients and 30 matched healthy controls. Deterministic tractography using multiple indices of diffusion (fractional anisotropy (FA), tract volume (Vol), tract length (Le) and number of tracts (NofT)) were obtained from the fornix, the cingulum, the anterior thalamic radiation, and the corpus callosum bilaterally. RESULTS: We showed widespread WM microstructural changes in SZ, and changes in the corpus callosum, the left cingulum and the fornix in BD. Fornix fiber tracking scores were associated with cognitive performance in SZ, and with age and age at disease onset in the BD patient group. LIMITATIONS: Although the influence of psychopharmacological drugs as biasing variables on morphological alterations has been discussed for SZ and BD, we did not observe a clear influence of drug exposure on our findings. CONCLUSIONS: These results confirm the assumption that SZ patients have more severe WM changes than BD patients. The findings also suggest a major role of WM changes in the fornix as important fronto-limbic connections in the etiology of cognitive symptoms in SZ, but not in BD.

Delayed restraint procedure enhances cognitive recovery of spatial function after fimbria-fornix transection.

PURPOSE: To i) evaluate the effect of a restraint procedure (7 days, 2 h/day) on place learning after fimbria-fornix transection (FF), ii) investigate effects of early vs. late administration of restraint, and iii) establish effects of the restraint procedure on expression of brain derived neurotrophic factor (BDNF) in prefrontal cortex and hippocampus. METHODS: Fifty rats subjected to FF or sham surgery and divided into groups exposed to restraint immediately (early restraint) or 21 days (late restraint) after surgery were trained to acquire an allocentric place learning task. In parallel, 29 animals were subjected to FF or sham surgery and an identical restraint procedure in order to measure concentrations of BDNF and corticosterone. RESULTS: The performance of the sham operated rats was positively affected by the late restraint. In FF-lesioned animals, the late restraint significantly improved task performance compared to the lesioned group with no restraint, while the early restraint was associated with a negative impact on task acquisition. Biochemical analysis after restraint procedure revealed a lesion-induced upregulation of BDNF in FF animals. CONCLUSIONS: The improved task performance of lesioned animals suggests a therapeutic effect of this manipulation, independent of BDNF. This effect is sensitive to the temporal administration of treatment.

Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice.

Deep brain stimulation (DBS) has improved the prospects for many individuals with diseases affecting motor control, and recently it has shown promise for improving cognitive function as well. Several studies in individuals with Alzheimer disease and in amnesic rats have demonstrated that DBS targeted to the fimbria-fornix, the region that appears to regulate hippocampal activity, can mitigate defects in hippocampus-dependent memory. Despite these promising results, DBS has not been tested for its ability to improve cognition in any childhood intellectual disability disorder. Such disorders are a pressing concern: they affect as much as 3% of the population and involve hundreds of different genes. We proposed that stimulating the neural circuits that underlie learning and memory might provide a more promising route to treating these otherwise intractable disorders than seeking to adjust levels of one molecule at a time. We therefore studied the effects of forniceal DBS in a well-characterized mouse model of Rett syndrome (RTT), which is a leading cause of intellectual disability in females. Caused by mutations that impair the function of MeCP2 (ref. 6), RTT appears by the second year of life in humans, causing profound impairment in cognitive, motor and social skills, along with an array of neurological features. RTT mice, which reproduce the broad phenotype of this disorder, also show clear deficits in hippocampus-dependent learning and memory and hippocampal synaptic plasticity. Here we show that forniceal DBS in RTT mice rescues contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restores in vivo hippocampal long-term potentiation and hippocampal neurogenesis. These results indicate that forniceal DBS might mitigate cognitive dysfunction in RTT.

Oligodendrogenesis in the fornix of adult mouse brain; the effect of LPS-induced inflammatory stimulation.

Evidence have been accumulated that continuous oligodendrogenesis occurs in the adult mammalian brain. The fornix, projection and commissure pathway of hippocampal neurons, carries signals from the hippocampus to other parts of the brain and has critical role in memory and learning. However, basic characterization of adult oligodendrogenesis in this brain region is not well understood. In the present study, therefore, we aimed to examine the proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) and the effect of acute inflammatory stimulation on oligodendrogenesis in the fornix of adult mouse. We demonstrated the proliferation of OPCs and a new generation of mature oligodendrocytes by using bromodeoxyuridine and Ki67 immunohistochemistry. Oligodendrogenesis of adult fornix was also demonstrated by using oligodendrocyte transcription factor 2 transgenic mouse. A single systemic administration of lipopolysaccharide (LPS) attenuated proliferation of OPCs in the fornix together with reduced proliferation of hippocampal neural stem/progenitor cells. Time course analysis showed that a single administration of LPS attenuated the proliferation of OPCs during 24-48 h. On the other hand, consecutive administration of LPS did not suppress proliferation of OPCs. The treatment of LPS did not affect differentiation of OPCs into mature oligodendrocytes. Treatment of a microglia inhibitor minocycline significantly attenuated basal proliferation of OPCs under normal condition. In conclusion, the present study indicates that continuous oligodendrogenesis occurs and a single administration of LPS transiently attenuates proliferation of OPCs without changing differentiation in the fornix of the adult mouse brains.