Background: The neuroanatomical substrates of Parkinson's disease (PD) with tremor‐dominance (TD) and those with non‐tremor dominance (nTD), postural instability and gait difficulty (PIGD), and akinetic‐rigid (AR) are not fully differentiated. A better understanding of symptom specific pathoanatomical markers of PD subtypes may result in earlier diagnosis and more tailored treatment. Here, we aim to give an overview of the neuroimaging literature that compared PD motor subtypes.Methods: A systematic literature review on neuroimaging studies of PD subtypes was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Search terms submitted to the PubMed database included: “Parkinson's disease”, “MRI” and “motor subtypes” (TD, nTD, PIGD, AR). The results are first discussed from macro to micro level of organization (i.e., (1) structural; (2) functional; and (3) molecular) and then by applied imaging methodology.Findings: Several neuroimaging methods including diffusion imaging and positron emission tomography (PET) distinguish specific PD motor subtypes well, although findings are mixed. Furthermore, our review demonstrates that nTD‐PD patients have more severe neuroalterations compared to TD‐PD patients. More specifically, nTD‐PD patients have deficits within striato‐thalamo‐cortical (STC) circuitry and other thalamocortical projections related to cognitive and sensorimotor function, while TD‐PD patients tend to have greater cerebello‐thalamo‐cortical (CTC) circuitry dysfunction.Conclusions: Based on the literature, STC and CTC circuitry deficits seem to be the key features of PD and the subtypes. Future research should make greater use of multimodal neuroimaging and techniques that have higher sensitivity in delineating subcortical structures involved in motor diseases.

Major depressive disorder (MDD) affects approximately 4.4% of the world’s population. One third of MDD patients do not respond to routine psychotherapeutic and pharmacotherapeutic treatment and are said to suffer from treatment-resistant depression (TRD). Deep brain stimulation (DBS) is increasingly being investigated as a treatment modality for TRD. Although early case studies showed promising results of DBS, open-label trials and placebo-controlled studies have reported inconsistent outcomes. This has raised discussion about the correct interpretation of trial results as well as the criteria for patient selection, the choice of stimulation target, and the optimal stimulation parameters. In this narrative review, we summarize recent studies of the effectiveness of DBS in TRD and address the relation between the targeted brain structures and clinical outcomes. Elaborating upon that, we hypothesize that the effectiveness of DBS in TRD can be increased by a more personalized and symptom-based approach. This may be achieved by using resting-state connectivity mapping for neurophysiological subtyping of TRD, by using individualized tractography to help decisions about stimulation target and electrode placement, and by using a more detailed registration of symptomatic improvements during DBS, for instance by using ‘experience sampling’ methods.

Aims: Women are more vulnerable to Alzheimer's disease (AD) than men. We investigated (i) whether and at what age the AD hallmarks, that is, β‐amyloid (Aβ) and hyperphosphorylated Tau (p‐Tau) show sex differences; and (ii) whether such sex differences may occur in cognitively intact elderly individuals.Methods: We first analysed the entire post‐mortem brain collection of all non‐demented ‘controls’ and AD donors from our Brain Bank (245 men and 403 women), for the presence of sex differences in AD hallmarks. Second, we quantitatively studied possible sex differences in Aβ, Aβ42 and p‐Tau in the entorhinal cortex of well‐matched female (n = 31) and male (n = 21) clinically cognitively intact elderly individuals.Results: Women had significantly higher Braak stages for tangles and amyloid scores than men, after 80 years. In the cognitively intact elderly, women showed higher levels of p‐Tau, but not Aβ or Aβ42, in the entorhinal cortex than men, and a significant interaction of sex with age was found only for p‐Tau but not Aβ or Aβ42.Conclusions: Enhanced p‐Tau in the entorhinal cortex may play a major role in the vulnerability to AD in women.

Deep brain stimulation is used to alleviate symptoms of neurological and psychiatric disorders including Parkinson’s disease, epilepsy, and obsessive–compulsive-disorder. Electrically stimulating limbic structures has been of great interest, and in particular, the region of the fornix. We conducted a systematic search for studies that reported clinical and preclinical outcomes of deep brain stimulation within the fornix up to July 2019. We identified 13 studies (7 clinical, 6 preclinical) that examined the effects of fornix stimulation in Alzheimer’s disease (n = 9), traumatic brain injury (n = 2), Rett syndrome (n = 1), and temporal lobe epilepsy (n = 1). Overall, fornix stimulation can lead to decreased rates of cognitive decline (in humans), enhanced memory (in humans and animals), visuo-spatial memorization (in humans and animals), and improving verbal recollection (in humans). While the exact mechanisms of action are not completely understood, studies suggest fornix DBS to be involved with increased functional connectivity and neurotransmitter levels, as well as enhanced neuroplasticity.

The neuropathological substrates of Parkinson’s disease (PD) patients with motor subtypes tremor-dominance (TD), non-tremor dominance (nTD), postural instability and gait difficulty (PIGD), and akinetic-rigid (AR) are not completely differentiated. While extensive pathological research has been conducted on neuronal tissue of PD patients, data have not been discussed in the context of mechanistic circuitry theories differentiating motor subtypes. It is, therefore, expected that a more specific and tailored management of PD symptoms can be accomplished by understanding symptom-specific neuropathological mechanisms with the detail histology can provide. This scoping review gives an overview of the literature comparing TD and nTD PD motor subtypes by clarify observed pathology with underlying physiological circuitry theories. Studies using an array of pathological examination techniques have shown significant differences between TD and nTD PD subtypes. nTD PD patients show higher neuronal loss, gliosis, extraneuronal melanin deposits, and neuroaxonal dystrophy in multiple subregions of the substantia nigra (SN) related to the overactivity of the indirect motor loop. TD patients show more severe cell loss specifically in medial SN subdivisions, and have damage in the retrorubral field A-8 that projects to the dorsolateral striatum and ventromedial thalamus in the direct motor loop. Pathological studies are consistent with neuroimaging data and support contemporary mechanistic circuitry theories of PD motor symptom genesis. Further multimodal neuroimaging and histological studies are required to validate and expand upon these findings.

The cerebellum, once primarily associated with motor functions, has emerged as a critical component in higher cognitive processes and emotional regulation. This paradigm shift frames the cerebellum as an essential focal point for elucidating sophisticated functional brain circuitry. Network neuroscience often maintains a cortical-centric viewpoint, potentially overlooking the significant contributions of the cerebellum in connectome organization. Enhanced recognition and integration of cerebellar aspects in connectomic analyses hold significant potential for elucidating cerebellar circuitry within comprehensive brain networks and in neuropsychiatric conditions where cerebellar involvement is evident. This review explores the intricate anatomy, connectivity, and functional organization of the cerebellum within the broader context of large-scale brain networks. Cerebellar-specific networks are examined, emphasizing their role in supporting diverse cognitive functions via the cerebellum's hierarchical functional organization. The clinical significance of cerebellar connectomics is then addressed, highlighting the interplay between cerebellar circuitry and neurological and psychiatric conditions. The paper concludes by considering neurostimulation treatments and future directions in the field. This comprehensive review underscores the cerebellum's integral role in the human connectome.